BRM and BRG1 targeting compounds and associated methods of use

Abstract

The present disclosure provides bifunctional compounds comprising a target protein binding moiety and a E3 ubiquitin ligase binding moiety, and associated methods of use.

Description

BRM AND BRG1 TARGETING COMPOUNDS AND ASSOCIATED METHODS OF USECROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U. S. Provisional Application Nos. 63 / 710,749, filed October 23, 2024, and 63 / 870,344, filed August 26, 2025, the entirety of each of which is incorporated by reference herein.TECHNICAL FIELD

[0002] The description provides bifunctional compounds comprising a target protein binding moiety and an E3 ubiquitin ligase binding moiety, and associated methods of use. The bifunctional compounds are useful as modulators of targeted ubiquitination, especially with respect to Switch / Sucrose Non-Fermentable (SWI / SNF)-Related, Matrix-Associated, Actin-Dependent Regulator of Chromatin, Subfamily A, Member 2 (SMARCA2) (i.e. BRAHMA or BRM), which are degraded and / or otherwise inhibited by bifunctional compounds according to the present disclosure.BACKGROUND

[0003] The human SWItch / Sucrose Non-Fermentable (SWI / SNF) complexes are ATP-dependent chromatin remodelers. These large complexes play important roles in essential cellular processes, such as transcription, DNA repair and replication by regulating DNA accessibility.

[0004] Mutations in the genes encoding up to 20 canonical SWI / SNF subunits are observed in nearly 20% of all human 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.

[0005] SMARCA2 (BRM) and SMARCA4 (BRG1) are the subunits containing catalytic ATPase domains and they are essential for the function of SWI / SNF in perturbation of histone-DNA contacts, thereby providing access points to transcription factors and cognate DNA elements that facilitate gene activation and repression.

[0006] SMARCA2 and SMARCA4 shares a high degree of homology (up to 75%). SMARCA4 is frequently mutated in primary tumors (i.e., deleted or inactivated), particularly in lung cancer (12%), melanoma, liver cancer and pancreatic cancer.

[0007] Previous studies have demonstrated the strong synthetic lethality using gene expression manipulation such as RNAi; downregulating SMARCA2 gene expression in SMARCA4 mutated cancer cells results in suppression of cancer cell proliferation. However, SMARCA2 / 4 bromodomain inhibitors (e.g. PFI-3) exhibit none to minor effects on cell proliferation inhibition [Vangamudi et al. Cancer Res 2015], This phenotypic discrepancy between gene expression downregulation and small molecule-based approach lead us to investigating protein degradation bispecific molecules in SMARCA4 deficient cancers.

[0008] Therapeutic compounds that inhibit SMARCA2 and / or SMARCA4 are needed.SUMMARY

[0009] The present disclosure is directed to a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:, (2S,4R)-4-hydroxy-l-((R)-2-(3-(2-(4-((6R,6aS)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[T,2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide;(2S,4R)-4-hydroxy-l-((R)-2-(3-(2-(4-((6S,6aR)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide;Compound V, which had the chemical name (3R,5S)-l-((R)-2-(3-(2-(4-((6S,6aS)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl dihydrogen phosphate; orCompound VI, (2-((65,6a5)-8-(l-(2-((5-((7?)- l-((25,47?)-4-Hydroxy-2-(((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)-pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-yl)isoxazol-3-yl)oxy)ethyl)piperidin-4-yl)-6-methyl-6,6a,7,8,9,10- hexahydro-5 / / -pyrazino[ l',2':4,5]-pyrazino[2,3-c]pyridazin-2-yl)phenoxy)methyl dihydrogen phosphate; orCompound XIII, (25,47?)-l-((7?)-2-(3-(2- (4-(((5)-2-(3-Fluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8Z / -pyrazino[r,2':4,5]pyrazino- [2,3-c]pyridazin-8-yl)methyl)piperidin-l-yl)-ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4- hydroxy-7V-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; orCompound XIV, (37?,5S)-l-((7?)-2-(3-(2-(4- ((5)-6a-Ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl dihydrogen phosphate.DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0010] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. The terminology used in the description is for describing particular embodiments only and is not intended to be limiting of the disclosure.[OH] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise (such as in the case of a group containing a number of carbon atoms in which case each carbon atom number falling within the range is provided), between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the disclosure.

[0012] The following terms are used to describe the present disclosure. In instances where a term is not specifically defined herein, that term is given an art -recognized meaning by those of ordinary skill applying that term in context to its use in describing the present disclosure.

[0013] The articles “a” and “an” as used herein and in the appended claims are used herein to refer to one or to more than one (e.g., to at least one) of the grammatical object of the article unless the context clearly indicates otherwise. By way of example, “an element” means one element or more than one element.

[0014] The terms “co-administration” and “co-administering” or “combination therapy” refer to both concurrent administration (administration of two or more therapeutic agents at the same time) and time varied administration (administration of one or more therapeutic agents at a time different from that of the administration of an additional therapeutic agent or agents), as long as the therapeutic agents are present in the patient to some extent, preferably at effective amounts, at the same time. In certain preferred aspects, one or more of the present compounds described herein, are co-administered in combination with at least one additional bioactive agent, especially including an anticancer agent. In particularly preferred aspects, the co-administration of compounds results in synergistic activity and / or therapy, including anticancer activity.

[0015] The term “ubiquitin ligase” refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein, targeting the substrate protein for degradation. For example, an E3 ubiquitin ligase protein that alone or in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein, andsubsequently targets the specific protein substrates for degradation by the proteasome. Thus, E3 ubiquitin ligase alone or in complex with an E2 ubiquitin conjugating enzyme is responsible for the transfer of ubiquitin to targeted proteins. In general, the ubiquitin ligase is involved in polyubiquitination such that a second ubiquitin is attached to the first; a third is attached to the second, and so forth. Polyubiquitination marks proteins for degradation by the proteasome.However, there are some ubiquitination events that are limited to mono-ubiquitination, in which only a single ubiquitin is added by the ubiquitin ligase to a substrate molecule. Mono-ubiquitinated proteins are not targeted to the proteasome for degradation but may instead be altered in their cellular location or function, for example, via binding other proteins that have domains capable of binding ubiquitin. Further complicating matters, different lysines on ubiquitin can be targeted by an E3 to make chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to make polyubiquitin, which is recognized by the proteasome.

[0016] The term “patient” or “subject” is used throughout the specification to describe an animal, preferably a human or a domesticated animal, to whom treatment, including prophylactic treatment, with the compositions according to the present disclosure is provided. For treatment of those infections, conditions or disease states which are specific for a specific animal such as a human patient, the term patient refers to that specific animal, including a domesticated animal such as a dog or cat or a farm animal such as a horse, cow, sheep, etc. In general, in the present disclosure, the term patient refers to a human patient unless otherwise stated or implied from the context of the use of the term.

[0017] The term “effective” is used to describe an amount of a compound, composition or component which, when used within the context of its intended use, effects an intended result. The term effective subsumes all other effective amount or effective concentration terms, which are otherwise described or used in the present application.

[0018] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U. S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, e.g., in humans.

[0019] “Pharmaceutically acceptable salt” refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed withinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3 -(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2 -hydroxy ethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

[0020] A “pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith.Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0021] A “solvate” refers to a physical association of a compound of the disclosure with one or more solvent molecules.

[0022] “Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (e.g., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treating” or “treatment” refers to delaying the onset of the disease or disorder.

[0023] Isotopic variants of the compounds of the disclosure (including all subgenera described herein) are also contemplated by the present disclosure.

[0024] It is to be appreciated that certain features of the invention which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless obviously incompatible or specifically excluded, each individual embodiment is deemed to be combinable with any other embodiment s) and such a combination is considered to be another embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination. While an embodiment may be described as part of a series of steps or part of a more general structure, each said step may also be considered an independent embodiment in itself, combinable with others.

[0025] In some aspects, the disclosure provides a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:, Compound I, which has the chemical name (2S,4R)-4-hydroxy-l-((R)-2-(3-(2-(4-((6S,6aS)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10- hexahydro-8H-pyrazino[r,2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5- yl)-3-methylbutanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide.

[0026] In some aspects, the disclosure provides a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:, Compound II, which has the chemical name (2S,4R)-4-hydroxy-l-((R)-2-(3-(2-(4-((6R,6aS)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10- hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5- yl)-3-methylbutanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide.

[0027] In other aspects, the disclosure provides a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:, Compound III, which has the chemical name (2S,4R)-4-hydroxy-l-((R)-2-(3-(2-(4-((6R,6aR)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[r,2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide.

[0028] In other aspects, the disclosure provides a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:, Compound IV, which has the chemical name (2S,4R)-4-hydroxy-l-((R)-2-(3-(2-(4-((6S,6aR)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide.

[0029] In yet other aspects, the disclosure provides a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:, Compound V, which has the chemical name (3R,5S)-l-((R)-2-(3-(2-(4-((6S,6aS)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl dihydrogen phosphate.

[0030] In yet other aspects, the disclosure provides a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:Compound VI, which has the chemical name (2-((65,6a5)-8-(l-(2-((5-((7?)-l-((25,47?)-4-Hydroxy-2-(((5)-l-(4-(4-methylthiazol-5-yl)phenyl)-ethyl)carbamoyl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-yl)isoxazol-3-yl)oxy)ethyl)piperidin-4-yl)-6-methyl-6,6a,7,8,9,10-hexahydro-5Z7-pyrazino[r,2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenoxy)methyl dihydrogen phosphate.

[0031] In yet other aspects, the disclosure provides a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:, Compound VII, which has the chemical name (3R, 55)- 1 -((R)-2-(3 -(2-(4-((67?, 6a5)-2-(2-hy droxyphenyl)-6-methyl-5, 6, 6a, 7, 9, 10-hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl dihydrogen phosphate.

[0032] In yet other aspects, the disclosure provides a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:Compound VIII, which has the chemical name (2-((67?,6a5)-8-(l-(2-((5-((7?)-l-((2£,47?)-4-Hydroxy-2-(((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-yl)isoxazol-3-yl)oxy)- ethyl)piperidin-4-yl)-6-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenoxy)-methyl dihydrogen phosphate.

[0033] In yet other aspects, the disclosure provides a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:, Compound IX, which has the chemical name (3R,5S)-l-((R)-2-(3-(2-(4-((6R,6aR)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl dihydrogen phosphate.

[0034] In yet other aspects, the disclosure provides a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:Compound X, which has the chemical name (2-((67?,6a7?)-8-(l-(2-((5-((7?)-l-((25',47?)-4-Hydroxy-2-(((5)-l-(4-(4-methylthiazol-5-yl)phenyl)- ethyl)carbamoyl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-yl)isoxazol-3-yl)oxy)ethyl)piperidin-4-yl)-6-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenoxy)-methyl dihydrogen phosphate.

[0035] In yet other aspects, the disclosure provides a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:, Compound XI, which has the chemical name (3R,5S)-l-((R)-2-(3-(2-(4-((6S,6aR)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl dihydrogen phosphate.

[0036] In yet other aspects, the disclosure provides a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:Compound XII, which has the chemical name (2-((65,6a7?)-8-(l-(2-((5-((7?)-l-((25,47?)-4-Hydroxy-2-(((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-yl)isoxazol-3-yl)oxy)ethyl)piperidin-4-yl)-6-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenoxy)-methyl dihydrogen phosphate.

[0037] In yet other aspects, the disclosure provides a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:Compound XIII, which has the chemical name (25,4 / ?)- 1 -((R)-2-(3 -(2-(4-(((5)-2-(3 -Fluoro-2-hy droxyphenyl)-5, 6, 6a, 7, 9, 10-hexahydro- 8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)-ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0038] In yet other aspects, the disclosure provides a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:Compound XIV, which has the chemical name (3R,5S)-1-((R)-2-(3-(2-(4-((S)-6a-Ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl dihydrogen phosphate.

[0039] In yet other aspects, the disclosure provides a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:name (3R,5S)-l-((R)-2-(3-(2-(4-(((S)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro- 8H-pyrazino[r,2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-l-yl)ethoxy)isoxazol-5-yl)- 3-methylbutanoyl)-5-(((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl dihydrogen phosphate.

[0040] In yet other aspects, the disclosure provides a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:Compound XVI, which has the chemical name (2S,4R)-l-((R)-2-(3-(2-(4-((S)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[r,2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0041] In yet other aspects, the disclosure provides a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:Compound XVII, which has the chemical name (2S,4R)-l-((R)-2-(3-(2-(4-((R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0042] In yet other aspects, the disclosure provides a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:Compound XVIII, which has the chemical name (3R,5S)-l-((R)-2-(3-(2-(4-((R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl dihydrogen phosphate.Pharmaceutical Compositions and Methods of Administration

[0043] In some aspects, the disclosure provides a pharmaceutical composition comprising Compound I, Compound II, Compound III, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, Compound XI, Compound XII, Compound XIII, Compound XIV, Compound XV, Compound XVI, Compound XVII, Compound XVIII, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0044] In some aspects, the disclosure provides a pharmaceutical composition comprising Compound I, Compound II, Compound III, Compound IV, Compound V, Compound VI,Compound VII, Compound VIII, Compound IX, Compound X, Compound XI, Compound XII, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0045] In some aspects, the disclosure provides a pharmaceutical composition comprising Compound I, Compound II, Compound III, Compound IV, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0046] In some aspects, the disclosure provides a pharmaceutical composition comprising Compound I, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0047] In some aspects, the disclosure provides a pharmaceutical composition comprising Compound II, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0048] In some aspects, the disclosure provides a pharmaceutical composition comprising Compound III, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0049] In some aspects, the disclosure provides a pharmaceutical composition comprising Compound IV, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0050] In some aspects, the disclosure provides a pharmaceutical composition comprising Compound V, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0051] In some aspects, the disclosure provides a pharmaceutical composition comprising Compound VI, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0052] In some aspects, the disclosure provides a pharmaceutical composition comprising Compound VII, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0053] In some aspects, the disclosure provides a pharmaceutical composition comprising Compound VIII, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0054] In some aspects, the disclosure provides a pharmaceutical composition comprising Compound IX, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0055] In some aspects, the disclosure provides a pharmaceutical composition comprising Compound X, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0056] In some aspects, the disclosure provides a pharmaceutical composition comprising Compound XI, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0057] In some aspects, the disclosure provides a pharmaceutical composition comprising Compound XII, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0058] In some aspects, the disclosure provides a pharmaceutical composition comprising Compound XIII, Compound XIV, Compound XV, Compound XVI, Compound XVII, Compound XVIII, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0059] In some aspects, the disclosure provides a pharmaceutical composition comprising Compound XIII, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0060] In some aspects, the disclosure provides a pharmaceutical composition comprising Compound XIV, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0061] In some aspects, the disclosure provides a pharmaceutical composition comprising Compound XV, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0062] In some aspects, the disclosure provides a pharmaceutical composition comprising Compound XVI, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0063] In some aspects, the disclosure provides a pharmaceutical composition comprising Compound XVII, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0064] In some aspects, the disclosure provides a pharmaceutical composition comprising Compound XVIII, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0065] The subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a compound of the present disclosure as the active ingredient,or a pharmaceutically acceptable salt, or solvate (including hydrate) thereof. Where desired, the pharmaceutical compositions contain pharmaceutically acceptable salt and / or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.

[0066] The subject pharmaceutical compositions can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions. Where desired, the one or more compounds of the invention and other agent(s) may be mixed into a preparation or both components may be formulated into separate preparations to use them in combination separately or at the same time.

[0067] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions of the present invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number in the range defined by and including any two numbers above) w / w, w / v or v / v.

[0068] In some embodiments, the concentration of one or more compounds of the invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number in the range defined by and including any two numbers above) w / w, w / v, or v / v.

[0069] In some embodiments, the concentration of one or more compounds of the invention is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% toapproximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w / w, w / v or v / v.

[0070] In some embodiments, the concentration of one or more compounds of the invention is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w / w, w / v or v / v.

[0071] In some embodiments, the amount of one or more compounds of the invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g (or a number in the range defined by and including any two numbers above).

[0072] In some embodiments, the amount of one or more compounds of the invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g,, 0.15 g, 0.2 g,, 0.25 g, 0.3 g,, 0.35 g, 0.4 g,, 0.45 g, 0.5 g, 0.55 g, 0.6 g,, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5g, 7 g, 7.5g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g (or a number in the range defined by and including any two numbers above).

[0073] In some embodiments, the amount of one or more compounds of the invention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g-

[0074] The compounds according to the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. An exemplary dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

[0075] A pharmaceutical composition of the invention typically contains an active ingredient (e.g., a compound of the disclosure) of the present invention or a pharmaceutically acceptable salt and / or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including but not limited to inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.

[0076] Described below are non- limiting exemplary pharmaceutical compositions and methods for preparing the same.Pharmaceutical Compositions for Oral Administration.

[0077] In some embodiments, the invention provides a pharmaceutical composition for oral administration containing a compound of the invention, and a pharmaceutical excipient suitable for oral administration.

[0078] In some embodiments, the invention provides a solid pharmaceutical composition for oral administration containing: (i) an effective amount of a compound of the invention; optionally (ii) an effective amount of a second agent; and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further contains: (iv) an effective amount of a third agent.

[0079] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or nonaqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such dosage formscan be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients.Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and / or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0080] This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds. For example, water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf- life or the stability of formulations over time. Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms of the invention which contain lactose can be made anhydrous if substantial contact with moisture and / or humidity during manufacturing, packaging, and / or storage is expected. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.

[0081] An active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agentscan be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.

[0082] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.

[0083] Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

[0084] Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle. Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.

[0085] Lubricants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof. A lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.

[0086] When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and / or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

[0087] The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

[0088] Surfactant which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.

[0089] A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance (" HLB" value). Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.

[0090] Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (e.g., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, HLB value of asurfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.

[0091] Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium docusate; acyl lactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[0092] Within the aforementioned group, ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and diglycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[0093] Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP -phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl -2 -lactyl ate, stearoyl lactylate, succinylated monoglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, citric acid esters of mono / diglycerides, cholyl sarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof.

[0094] Hydrophilic non-ionic surfactants may include, but are not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyolwith at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

[0095] Other hydrophilic-non-ionic surfactants include, without limitation, PEG- 10 laurate, PEG- 12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG- 12 oleate, PEG- 15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate / caprylate glycerides, PEG-8 caprate / capryl ate glycerides, polyglyceryl- 10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE -23 lauryl ether, POE- 10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG- 100 succinate, PEG-24 cholesterol, polyglyceryl-10oleate, Tween 40, Tween 60, sucrose monostearate, sucrose mono laurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers.

[0096] Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oilsoluble vitamins / vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, andmixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0097] In one embodiment, the composition may include a solubilizer to ensure good solubilization and / or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This can be especially important for compositions for non-oral use, e.g., compositions for injection. A solubilizer may also be added to increase the solubility of the hydrophilic drug and / or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[0098] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, s-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyl tri ethyl citrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, a -caprolactone and isomers thereof, 6-valerolactone and isomers thereof, P-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water.

[0099] Mixtures of solubilizers may also be used. Examples include, but not limited to, triacetin, tri ethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.

[0100] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example to maximize the concentration ofthe drug, with excess solubilizer removed prior to providing the composition to a subject using conventional techniques, such as distillation or evaporation. Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%, 50%), 100%, or up to about 200%> by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer may also be used, such as 5%>, 2%>, 1%) or even less. Typically, the solubilizer may be present in an amount of about 1%> to about 100%, more typically about 5%> to about 25%> by weight.

[0101] The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0102] In addition, an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable are bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of polyprotic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.

[0103] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids,ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like.Pharmaceutical Compositions for Injection

[0104] In some embodiments, the invention provides a pharmaceutical composition for injection containing a compound of the present invention and a pharmaceutical excipient suitable for injection. Components and amounts of agents in the compositions are as described herein.

[0105] The forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0106] Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0107] Sterile injectable solutions are prepared by incorporating the compound of the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desirable methods of preparation are vacuum-drying and freeze- drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.Pharmaceutical Compositions for Topical (e.g., Transdermal) Delivery

[0108] In some embodiments, the invention provides a pharmaceutical composition for transdermal delivery containing a compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery.

[0109] Compositions of the present invention can be formulated into preparations in solid, semisolid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)-based solutions. In general, carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients. In contrast, a solution formulation may provide more immediate exposure of the active ingredient to the chosen area.

[0110] The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin. There are many of these penetration- enhancing molecules known to those trained in the art of topical formulation.

[0111] Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[0112] Another exemplary formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound of the present invention in controlled amounts, either with or without another agent.

[0113] The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U. S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.Pharmaceutical Compositions for Inhalation

[0114] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Theliquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.Other Pharmaceutical Compositions

[0115] Pharmaceutical compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical compositions are well-known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference herein in their entirety.

[0116] Administration of the compounds or pharmaceutical composition of the present invention can be affected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g. transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. Compounds can also be administered intraadiposally or intrathecally.

[0117] In some embodiments, the compounds or pharmaceutical composition of the present invention are administered by intravenous injection.

[0118] The amount of the compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in therange of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g / day, preferably about 0.05 to about 2.5 g / day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g. by dividing such larger doses into several small doses for administration throughout the day.

[0119] In some embodiments, a compound of the invention is administered in a single dose.

[0120] Typically, such administration will be by injection, e.g., intravenous injection, in order to introduce the agent quickly. However, other routes may be used as appropriate. A single dose of a compound of the invention may also be used for treatment of an acute condition.

[0121] In some embodiments, a compound of the invention is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, once every two weeks, once a week, or once every other day. In another embodiment a compound of the invention and another agent are administered together about once per day to about 6 times per day. In another embodiment the administration of a compound of the invention and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.

[0122] Administration of the compounds of the invention may continue as long as necessary. In some embodiments, a compound of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound of the invention is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.

[0123] An effective amount of a compound of the invention may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0124] The compositions of the invention may also be delivered via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer. Such a method of administration may, for example, aid in the prevention or amelioration of restenosis following procedures such as balloon angioplasty. Without being bound by theory, compounds of theinvention may slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall which contribute to restenosis. A compound of the invention may be administered, for example, by local delivery from the struts of a stent, from a stent graft, from grafts, or from the cover or sheath of a stent. In some embodiments, a compound of the invention is admixed with a matrix. Such a matrix may be a polymeric matrix and may serve to bond the compound to the stent. Polymeric matrices suitable for such use, include, for example, lactone-based polyesters or copolyesters such as polylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester) copolymers (e.g. PEO-PLLA); polydimethylsiloxane, poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g. polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone), fluorinated polymers such as polytetrafluoroethylene and cellulose esters. Suitable matrices may be nondegrading or may degrade with time, releasing the compound or compounds. Compounds of the invention may be applied to the surface of the stent by various methods such as dip / spin coating, spray coating, dip-coating, and / or brush-coating. The compounds may be applied in a solvent and the solvent may be allowed to evaporate, thus forming a layer of compound onto the stent.Alternatively, the compound may be located in the body of the stent or graft, for example in microchannels or micropores. When implanted, the compound diffuses out of the body of the stent to contact the arterial wall. Such stents may be prepared by dipping a stent manufactured to contain such micropores or microchannels into a solution of the compound of the invention in a suitable solvent, followed by evaporation of the solvent. Excess drug on the surface of the stent may be removed via an additional brief solvent wash. In yet other embodiments, compounds of the invention may be covalently linked to a stent or graft. To link compounds of the invention to the stent or graft, a covalent linker may be used which degrades in vivo, leading to the release of the compound from the stent. Compounds of the invention may additionally be administered intravascularly from a balloon used during angioplasty. Extravascular administration of the compounds via the pericard or via adventitial application of formulations of the invention may also be performed to decrease restenosis.

[0125] A variety of stent devices which may be used as described are disclosed, for example, in the following references, all of which are hereby incorporated by reference: U.S. Pat. No. 5451233; U.S. Pat. No. 5040548; U.S. Pat. No. 5061273; U.S. Pat. No. 5496346; U.S. Pat. No. 5292331; U.S. Pat. No. 5674278; U.S. Pat. No. 3657744; U.S. Pat. No. 4739762; U.S. Pat. No. 5195984; U.S. Pat. No. 5292331 ; U.S. Pat. No. 5674278; U.S. Pat. No. 5879382; U.S. Pat. No. 6344053.

[0126] The compounds of the invention may be administered in dosages. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing for a compound of the invention may be found by routine experimentation in light of the instant disclosure.

[0127] When a compound of the invention is administered in a composition that comprises one or more agents, and the agent has a shorter half- life than the compound of the invention unit dose forms of the agent and the compound of the invention may be adjusted accordingly.

[0128] The subject pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

[0129] Exemplary parenteral administration forms include solutions or suspensions of active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.Methods of Use

[0130] In some aspects, the disclosure provides methods of treating cancer in a subject in need thereof comprising administering to the subject Compound I, Compound II, Compound III, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, Compound XI, Compound XII, Compound XIII, Compound XIV, Compound XV, Compound XVI, Compound XVII, Compound XVIII, or a pharmaceutically acceptable salt or solvate thereof.

[0131] In some aspects, the disclosure provides methods of treating cancer in a subject in need thereof comprising administering to the subject Compound I, Compound II, Compound III, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, Compound XI, Compound XII, or a pharmaceutically acceptable salt or solvate thereof.

[0132] In some aspects, the disclosure provides methods of treating cancer in a subject in need thereof comprising administering to the subject Compound I, Compound II, Compound III, Compound IV, or a pharmaceutically acceptable salt or solvate thereof.

[0133] In some aspects, the disclosure provides methods of treating cancer in a subject in need thereof comprising administering to the subject Compound I, or a pharmaceutically acceptable salt or solvate thereof.

[0134] In some aspects, the disclosure provides methods of treating cancer in a subject in need thereof comprising administering to the subject Compound II, or a pharmaceutically acceptable salt or solvate thereof.

[0135] In some aspects, the disclosure provides methods of treating cancer in a subject in need thereof comprising administering to the subject Compound III, or a pharmaceutically acceptable salt or solvate thereof.

[0136] In some aspects, the disclosure provides methods of treating cancer in a subject in need thereof comprising administering to the subject Compound IV, or a pharmaceutically acceptable salt or solvate thereof.

[0137] In some aspects, the disclosure provides methods of treating cancer in a subject in need thereof comprising administering to the subject Compound V, or a pharmaceutically acceptable salt or solvate thereof.

[0138] In some aspects, the disclosure provides methods of treating cancer in a subject in need thereof comprising administering to the subject Compound VI, or a pharmaceutically acceptable salt or solvate thereof.

[0139] In some aspects, the disclosure provides methods of treating cancer in a subject in need thereof comprising administering to the subject Compound VII, or a pharmaceutically acceptable salt or solvate thereof.

[0140] In some aspects, the disclosure provides methods of treating cancer in a subject in need thereof comprising administering to the subject Compound VIII, or a pharmaceutically acceptable salt or solvate thereof.

[0141] In some aspects, the disclosure provides methods of treating cancer in a subject in need thereof comprising administering to the subject Compound IX, or a pharmaceutically acceptable salt or solvate thereof.

[0142] In some aspects, the disclosure provides methods of treating cancer in a subject in need thereof comprising administering to the subject Compound X, or a pharmaceutically acceptable salt or solvate thereof.

[0143] In some aspects, the disclosure provides methods of treating cancer in a subject in need thereof comprising administering to the subject Compound XI, or a pharmaceutically acceptable salt or solvate thereof.

[0144] In some aspects, the disclosure provides methods of treating cancer in a subject in need thereof comprising administering to the subject Compound XII, or a pharmaceutically acceptable salt or solvate thereof.

[0145] In some aspects, the disclosure provides methods of treating cancer in a subject in need thereof comprising administering to the subject Compound XIII, Compound XIV, Compound XV, Compound XVI, Compound XVII, Compound XVIII, or a pharmaceutically acceptable salt or solvate thereof.

[0146] In some aspects, the disclosure provides methods of treating cancer in a subject in need thereof comprising administering to the subject Compound XIII, or a pharmaceutically acceptable salt or solvate thereof.

[0147] In some aspects, the disclosure provides methods of treating cancer in a subject in need thereof comprising administering to the subject Compound XIV, or a pharmaceutically acceptable salt or solvate thereof.

[0148] In some aspects, the disclosure provides methods of treating cancer in a subject in need thereof comprising administering to the subject Compound XV, or a pharmaceutically acceptable salt or solvate thereof.

[0149] In some aspects, the disclosure provides methods of treating cancer in a subject in need thereof comprising administering to the subject Compound XVI, or a pharmaceutically acceptable salt or solvate thereof.

[0150] In some aspects, the disclosure provides methods of treating cancer in a subject in need thereof comprising administering to the subject Compound XVII, or a pharmaceutically acceptable salt or solvate thereof.

[0151] In some aspects, the disclosure provides methods of treating cancer in a subject in need thereof comprising administering to the subject Compound XVIII, or a pharmaceutically acceptable salt or solvate thereof.

[0152] The method typically comprises administering to a subject a therapeutically effective amount of a compound of the disclosure. The therapeutically effective amount of the compound may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one ofordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of proliferation or downregulation of activity of a target protein. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0153] In certain embodiment, the present invention provides a pharmaceutical composition comprising a compound of the disclosure, or pharmaceutically acceptable salt thereof.

[0154] In certain embodiment, the present invention provides a pharmaceutical composition comprising a compound of the disclosure for use in degrading a target protein in a cell.

[0155] In certain embodiment, a method of degrading a target protein comprising administering to a cell therapeutically effective amount of a compound of the disclosure, or pharmaceutically acceptable salt, wherein the compound is effective for degrading the target protein.

[0156] In some embodiments, the disclosure is directed to methods of degrading a SMARCA2 protein comprising contacting the SMARCA2 protein with a compound or pharmaceutical composition of the disclosure.

[0157] In other embodiments, the disclosure is directed to methods of degrading a SMARCA4 protein comprising contacting the SMARCA4 protein with a compound or pharmaceutical composition of the disclosure.

[0158] In certain embodiment, the present invention provides a pharmaceutical composition comprising a compound of the disclosure, for use in treating or preventing of a disease or disorder in which SMARCA2 and / or SMARCA4 plays a role.

[0159] In certain embodiment, the present invention provides a pharmaceutical composition comprising a compound of the disclosure, for use in treating or preventing of a disease or disorder in which SWI / SNF mutations plays a role.

[0160] In certain embodiment, target proteins are SMARCA2, SMARCA4 and / or PB1.

[0161] In certain embodiment, target protein complex is SWI / SNF in a cell.

[0162] In certain embodiment, diseases or disorders dependent on SMARCA2 or SMARCA4 include cancers.

[0163] In certain embodiment, diseases or disorders dependent on SWI / SNF complex include cancers.

[0164] 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, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinomas.

[0165] In some embodiments, the cancer which may be treated using compounds according to the present disclosure is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, soft tissue sarcoma, or penile cancer.

[0166] In other embodiments, cancers which may be treated using compounds according to the present disclosure include, for example, acute myeloid leukemia (AML), 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.

[0167] In certain further embodiment, the cancer is a SMARCA2 and / or SMARAC4 -dependent cancer.

[0168] In some embodiments, the cancer harbors a SMARCA4 mutation.

[0169] In certain embodiment, the present invention provides a pharmaceutical composition comprising a compound of the disclosure for use in the diseases or disorders dependent upon SMARCA2 and / or SMARCA4 is cancer.

[0170] Compounds of the disclosure, as well as pharmaceutical compositions comprising them, can be administered to treat any of the described diseases, alone or in combination with a medical therapy. Medical therapies include, for example, surgery and radiotherapy (e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, systemic radioactive isotopes).

[0171] In other aspects, compounds of the disclosure, as well as pharmaceutical compositions comprising them, can be administered to treat any of the described diseases, alone or in combination with one or more other agents.

[0172] In other methods, the compounds of the disclosure, as well as pharmaceutical compositions comprising them, can be administered in combination with agonists of nuclear receptors agents.

[0173] In other methods, the compounds of the disclosure, as well as pharmaceutical compositions comprising them, can be administered in combination with antagonists of nuclear receptors agents.

[0174] In other methods, the compounds of the disclosure, as well as pharmaceutical compositions comprising them, can be administered in combination with an anti-proliferative agent.Combination Therapies

[0175] In certain aspects, one or more of the compounds described herein, are co-administered in combination with at least one additional bioactive agent, especially including an anticancer agent. In particularly preferred aspects, the co-administration of compounds results in synergistic activity and / or therapy, including anticancer activity.

[0176] For treating cancer and other proliferative diseases, the compounds of the invention can be used in combination with chemotherapeutic agents, agonists or antagonists of nuclear receptors, or other anti-proliferative agents. The compounds of the invention can also be used in combination with a medical therapy such as surgery or radiotherapy, e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes. Examples of suitable chemotherapeutic agents include any of: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, all -trans retinoic acid, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bendamustine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate,etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panobinostat, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinstat and zoledronate.

[0177] In some embodiments, the compounds of the invention can be used in combination with a therapeutic agent that targets an epigenetic regulator. Examples of epigenetic regulators include bromodomain inhibitors, the histone lysine methyltransferase inhibitors, histone arginine methyl transferase inhibitors, histone demethylase inhibitors, histone deacetylase inhibitors, histone acetylase inhibitors, and DNA methyltransferase inhibitors. Histone deacetylase inhibitors include, e.g., vorinostat. Histone arginine methyl transferase inhibitors include inhibitors of protein arginine methyltransferases (PRMTs) such as PRMT5, PRMT1 and PRMT4. DNA methyltransferase inhibitors include inhibitors of DNMT1 and DNMT3.

[0178] For treating cancer and other proliferative diseases, the compounds of the invention can be used in combination with targeted therapies, including JAK kinase inhibitors (e.g. ruxolitinib), PI3 kinase inhibitors including PI3K-delta selective and broad spectrum PI3K inhibitors, MEK inhibitors, Cyclin Dependent kinase inhibitors, including CDK4 / 6 inhibitors and CDK9 inhibitors, BRAF inhibitors, mTOR inhibitors, proteasome inhibitors (e.g. bortezomib, carfilzomib), HD AC inhibitors (e.g. panobinostat, vorinostat), DNA methyl transferase inhibitors, dexamethasone, bromo and extra terminal family member (BET) inhibitors, BTK inhibitors (e.g. ibrutinib, acalabrutinib), BCL2 inhibitors (e.g. venetoclax), dual BCL2 family inhibitors (e.g. BCL2 / BCLxL), PARP inhibitors, FLT3 inhibitors, or LSD1 inhibitors.

[0179] In some embodiments, the compounds of the invention can be used in combination with an inhibitor of an immune checkpoint molecule, such as, for example, an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), or PDR001. In some embodiments, theanti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-Ll monoclonal antibody. In some embodiments, the anti-PD-Ll monoclonal antibody is atezolizumab, durvalumab, or BMS-935559. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab.

[0180] In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of an alkylating agent include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).

[0181] In some aspects, the disclosure provides Compound XIII, Compound XIV, Compound XV, Compound XVI, Compound XVII, or Compound XVIII, or a pharmaceutically acceptable salt or solvate of one of the foregoing compounds, for use as an analytical standard in an analytical method used to determine the presence or quantity of a different compound.

[0182] In some aspects, the disclosure provides Compound XIII, or a pharmaceutically acceptable salt or solvate thereof, for use as an analytical standard in an analytical method used to determine the presence or quantity of a different compound.

[0183] In some aspects, the disclosure provides Compound XIV, or a pharmaceutically acceptable salt or solvate thereof, for use as an analytical standard in an analytical method used to determine the presence or quantity of a different compound.

[0184] In some aspects, the disclosure provides Compound XV, or a pharmaceutically acceptable salt or solvate thereof, for use as an analytical standard in an analytical method used to determine the presence or quantity of a different compound.

[0185] In some aspects, the disclosure provides Compound XVI, or a pharmaceutically acceptable salt or solvate thereof, for use as an analytical standard in an analytical method used to determine the presence or quantity of a different compound.

[0186] In some aspects, the disclosure provides Compound XVII, or a pharmaceutically acceptable salt or solvate thereof, for use as an analytical standard in an analytical method used to determine the presence or quantity of a different compound.

[0187] In some aspects, the disclosure provides Compound XVIII, or a pharmaceutically acceptable salt or solvate thereof, for use as an analytical standard in an analytical method used to determine the presence or quantity of a different compound.Aspects of the Invention

[0188] In a first aspect of the invention, provided is a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:(2S,4R)-4-hydroxy-l-((R)-2-(3-(2-(4-((6S,6aS)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;(2S,4R)-4-hydroxy-l-((R)-2-(3-(2-(4-((6R,6aS)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;(2S,4R)-4-hydroxy-l-((R)-2-(3-(2-(4-((6R,6aR)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; or(2S,4R)-4-hydroxy-l-((R)-2-(3-(2-(4-((6S,6aR)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0189] In a second aspect of the invention, provided is a compound of the first aspect, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:(2S,4R)-4-hydroxy-l-((R)-2-(3-(2-(4-((6S,6aS)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0190] In a third aspect of the invention, provided is a compound of the first aspect, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:(2S,4R)-4-hydroxy-l-((R)-2-(3-(2-(4-((6R,6aS)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0191] In a fourth aspect of the invention, provided is a compound of the first aspect, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:(2S,4R)-4-hydroxy-l-((R)-2-(3-(2-(4-((6R,6aR)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0192] In a fifth aspect of the invention, provided is a compound of the first aspect, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:(2S,4R)-4-hydroxy-l-((R)-2-(3-(2-(4-((6S,6aR)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0193] In a sixth aspect of the invention, provided is a compound of any one of the previous aspects, in the form of a pharmaceutically acceptable salt.

[0194] In a seventh aspect of the invention, provided is a compound of any one of the previous aspects, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0195] In an eighth aspect of the invention, provided is a method of treating cancer in a subject in need thereof, comprising administering to the patient a compound of any one of the first through sixth aspects, or a pharmaceutically acceptable salt thereof, or a composition of the seventh aspect.

[0196] In a ninth aspect of the invention, provided is a method of the seventh aspect, wherein the cancer is 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, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinomas.

[0197] In a tenth aspect of the invention, provided is a method of the eighth aspect, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, soft tissue sarcoma, or penile cancer.

[0198] In an eleventh aspect of the invention, provided is a method of the eighth through tenth aspects, wherein the cancer is acute myeloid leukemia (AML), 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.

[0199] In a twelfth aspect of the invention, provided is a method of degrading a SMARCA2 protein comprising contacting the SMARCA2 protein with a compound of any one of the first through sixth aspects, or a pharmaceutically acceptable salt thereof, or a composition of the seventh aspect.

[0200] In a thirteenth aspect of the invention, provided is a method of degrading a SMARCA4 protein comprising contacting the SMARCA4 protein with a compound of any one of the first through sixth aspects, or a pharmaceutically acceptable salt thereof, or a composition of the seventh aspect.

[0201] The following Examples are provided to illustrate some of the concepts described within this disclosure. While the Examples are considered to provide an embodiment, it should not be considered to limit the more general embodiments described herein.EXAMPLES

[0202] The compounds of the Invention may be prepared using the procedures described below.Intermediate 1:Butyl (61?,6a»S)-2-chloro-6-methyl-5,6,6a,7,9,10-hexahydro-8Z / -pyrazino [1 ',2': 4,5] pyrazino [2,3-c] pyridazine-8-carboxylateIntermediate 2: tert-Butyl (6. S.6a. S)-2-chloio-6-inethyl-5.6.6a.7.9.10-hexahydro-S / / -pyrazino [1 ',2': 4,5] pyrazino [2,3-c] pyridazine-8-carboxylate

[0203] Step 1: tert-Butyl (S)-4-(3, 6-dichloropyridazin-4-yl)-3-(hydroxymethyl)-piperazine-l-carboxylate

[0204] To tert-butyl (5)-3-(hydroxymethyl)piperazine-l -carboxylate (2.90 g, 13.4 mmol) and 3,4,6-trichloropyridazine (2.00 g, 10.9 mmol) in DMSO (20 mL) was added N, N-diisopropylethylamine (2.85 mL, 16.4 mmol). The reaction was stirred at 80 °C overnight then allowed to cool to rt. The reaction was diluted with water (~50 mL) and stirred vigorously and sonicated. The solid was filtered and washed with water and hexanes to afford the title compound (3.21 g, 81%) as a beige solid. LCMS calc, for C14H21CI2N4O3 [M+H]+: m / z = 363.1; Found: 363.0.

[0205] Step 2: tert-Butyl (S)-4-(3, 6-dichloropyridazin-4-yl)-3-formylpiperazine-l -carboxylate

[0206] To a solution of tert-butyl (5)-4-(3,6-dichloropyridazin-4-yl)-3-(hydroxy-methyl)-piperazine-1 -carboxylate (1.50 g, 4.13 mmol) in DCM (30 mL) at 0 °C was added Dess-Martin periodinane (2.45 g, 5.78 mmol), portion-wise, over 2 min. The reaction was stirred at rt for 50min then concentrated to —1 / 4 volume and purified via SiC>2 FCC (0-60% EtOAc in hexanes) to afford the title compound (1.107 g, 74%) as a yellow solid. LCMS calc, for C14H19CI2N4O3 [M+H]+: m / z = 361.1; Found: 360.9.

[0207] Step 3 tert-Butyl (3S)-4-(3,6-dichloropyridazin-4-yl)-3-(l-hydroxyethyl)-3-methyl-piperazine-1 -carboxylate

[0208] To a solution of tert-butyl (5)-4-(3,6-dichloropyridazin-4-yl)-3-formyl-piperazine-l- carboxylate (1.10 g, 3.04 mmol) in THF (35 mL) at 0 °C was added MeMgBr (7.29 mL, 9.11 mmol) dropwise. The reaction was stirred at 0 °C for 35 min then quenched slowly with sat. NH4CI (aq.). The reaction was poured into water and EtOAc was added. The layers were separated, and the aqueous layer was extracted once with EtOAc. The combined organic layers were dried with MgSO4, filtered, and concentrated. The crude residue was purified via SiO? FCC (0-60% EtOAc in hexanes) to afford tert-butyl (3S)-4-(3,6-dichloropyridazin-4-yl)-3-(l-hydroxyethyl)-3 -methylpiperazine- 1 -carboxylate (783 mg, 68%) as a yellow solid. LCMS calc, for C15H23CI2N4O3 [M+H]+: m / z = 377.1; Found: 377.0.

[0209] Step 4: tert-Butyl (6R,6aS)-2-chloro-6-methyl-5,6,6a, 7,9, 10-hexahydro-8H-pyrazino-[l',2 4, 5 ]pyrazino[ 2, 3-c ]pyridazine-8-carboxylate andtert-butyl ( 6S, 6aS)-2-chloro-6-methyl-5, 6, 6a, 7, 9, 10-hexahydro-8H-pyrazino [ 1 ', 2 ':4, 5 Jpyrazino-[2, 3-c ]pyridazine-8-carboxylate

[0210] To a solution of tert-butyl (35)-4-(3,6-dichloropyridazin-4-yl)-3-(l-hydroxy-ethyl)-3-m ethylpiperazine- 1 -carboxylate (783 mg, 2.08 mmol) and PPI13 (817 mg, 3.11 mmol) in THF (20 mL) at 0 °C was added diisopropyl azodicarboxylate (0.613 mL, 3.11 mmol), followed by DPPA (1.12 mL, 5.19 mmol). The reaction was stirred at rt for 40 min then treated with additional PPI13 (1.63 g, 6.23 mmol). The reaction was stirred at 60 °C for 1 h, after which A'A -di isop ropy 1- ethylamine (1.81 mL, 10.4 mmol) and water (3 mL) were added. The reaction was stirred at 60 °C overnight then allowed to cool to rt. The resulting residue was purified via SiCh FCC (0-10% MeOH in DCM) then chiral semi-prep to afford the title compound (Intermediate 1; 104 mg, 15%); LCMS calc, for C15H23CIN5O2 [M+H]+: m / z = 340.2; Found: 340.0; *HNMR (400 MHz, DMSO) 87.24 (s, 1H), 6.74 (s, 1H), 3.99 - 3.87 (m, 2H), 3.87 - 3.80 (m, 1H), 3.68 - 3.58 (m,1H), 3.01 -2.84 (m, 2H), 2.75 - 2.54 (m, 1H), 1.41 (s, 9H), 1.12 (d, J= 6.5 Hz, 3H), note: significant overlap observed between one proton peak (63.28 - 3.35 (m)) and residual water peak; and the title compound (Intermediate 2; 111 mg, 16%). LCMS calc, for C15H23CIN5O2 [M+H]+: m / z = 340.2; Found: 340.1; *HNMR (400 MHz, DMSO) 87.31 (s, 1H), 6.69 (s, 1H), 4.15 - 3.98 (m, 1H), 3.98 - 3.86 (m, 1H), 3.85 - 3.74 (m, 1H), 3.32 - 3.22 (m, 1H), 3.05 - 2.89 (m, 1H), 2.89 - 2.74 (m, 2H), 2.72 - 2.53 (m, 1H), 1.42 (s, 9H), 1.19 (d, J= 6.2 Hz, 3H).

[0211] The following chiral semi-prep conditions can be used: Lux IA3, starting at 50% 1:1 IPA: MeOH at 30 mL / min, -125 bar; Intermediate 1 retention time: 3.26 min; Intermediate 2 retention time: 4.86 min.

[0212] Alternatively, the following chiral semi-prep conditions could be used: Lux Cellulose-4, 50:25:25 hexanes: IPA: MeOH at 30 mL / min; Intermediate 1 retention time: 6.2 min;Intermediate 2 retention time: 9.7 min.Intermediate 3: tert- Butyl (6. S.6:i / ?)-2-chloro-6-inethyl-5.6.6a.7.9.10-hexahydro-8 / / -pyrazino [1 ',2': 4,5] pyrazino [2,3-c] pyridazine-8-carboxylateIntermediate 4: tert- Butyl (6 / ?.6a / ?)-2-chloro-6-inethyl-5.6.6a.7.9.10-hexahydro-8 / / -pyrazino [1 ',2': 4,5] pyrazino [2,3-c] pyridazine-8-carboxylate

[0213] The title compounds (Intermediate 3 and Intermediate 4) were prepared using procedures analogous to those used to synthesize Intermediate 1 and Intermediate 2, starting with tert-butyl ( / ?)-3 -(hydroxymethyl )piperazine-l -carboxylate instead of tert-butyl fS')-3-(hydroxymethyl)piperazine-l -carboxylate. Intermediate 3: LCMS calc, for C15H23CIN5O2 [M+H]+: m / z = 340.2; Found: 340.1. Retention time: 1.020 min (CSH Fluoro-Phenyl, 2.1x50 mm, 1.7 pm, 2-100% MeCN (0.025% TFA (aq.)) over 1.8 min at 1 mL / min). Intermediate 4:LCMS calc, for C15H23CIN5O2 [M+H]+: m / z = 340.2; Found: 340.0. Retention time: 1.048 min(CSH Fluoro-Phenyl, 2.1x50 mm, 1.7 pm, 2-100% MeCN (0.025% TFA (aq.)) over 1.8 min at 1 mL / min).Intermediate 5: 2-((6 / L 6a5)-6-Methyl-8-(piperidin-4-yl)-6, 6a, 7,8,9, 10-hexahydro-5 / / - pyrazino [1 ',2': 4,5] pyrazino [2, 3-c] pyridazin-2-yl)phenol

[0214] Step 1: 2-((6R,6aS)-6-Methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazmo[l',2':4,5]-pyrazino[ 2, 3-c ]pyridazin-2-yl)phenol

[0215] A mixture of tert-butyl (6A,6a5)-2-chloro-6-methyl-5,6,6a,7,9,10-hexahydro-8JT-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (Intermediate 1; 30.0 mg, 88.3 pmol), 2-hydroxyphenylboronic acid (24.4 mg, 0.177 mmol), XPhos Pd G2 (6.95 mg, 8.83 pmol) and K3PO4 (56.2 mg, 0.265 mmol) in 1,4-dioxane (1.8 mL) and water (0.2 mL) was stirred at 100 °C for 2 h. The reaction was cooled to rt, concentrated and the crude residue was purified via prep-HPLC on a C18 column (10-40% MeCN / 0.05% TFA (aq.)). The fraction containing the desired product was concentrated and the resulting residue was treated with TFA (2 mL), concentrated, and lyophilized to afford the TFA salt of the title compound (56.1 mg, 99%) as a brown solid. LCMS calc, for C16H20N5O [M+H]+m / z= 298.2; Found 298.3.

[0216] Step 2: 2-((6R,6aS)-6-Methyl-8-(piperidin-4-yl)-6,6a, 7,8,9, 10-hexahydro-5H-pyrazino-[l',2 4, 5 ] pyrazino [ 2, 3-c ]pyridazin-2-yl)phenol

[0217] To a solution of 2-((6A,6a5)-6-methyl-6,6a,7,8,9, 10-hexahydro-5Z7-pyrazino- [l',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol TFA salt (45.9 mg, 0.0718 mmol), tert-butyl 4- oxo-piperi dine- 1 -carboxylate (28.6 mg, 0.144 mmol) and A, A-diisopropylethylamine (62.5 pL, 0.359 mmol) in DCE (2.0 mL) was added sodium triacetoxyborohydride (30.4 mg, 0.144 mmol). The reaction was stirred at rt for 16 h then treated with sat. NaHCCh (aq.) (3.0 mL) and DCM (3.0 mL). The layers were separated, and the aqueous phase was extracted with DCM (3 x 3 mL).The combined organic layers were dried over Na2SC>4 and concentrated. The crude material was purified via prep-HPLC on a C18 column (10-40% MeCN / 0.05% TFA (aq.)), after which fractions containing the desired product were concentrated. The resulting residue was treated with TFA (2 mL) then concentrated to give the TFA salt of the title compound (15.7 mg, 26%) as a brown solid. LCMS calc, for C21H29N6O [M+H]+m / z= 381.2; Found 381.4.Intermediate 6: 2-((6. S'.6a5)-6-Methyl-8-(piperidin-4-yl)-6, 6a, 7,8,9, 10-hexahydro-5H- pyrazino [1 ',2': 4,5] pyrazino [2, 3-c] pyridazin-2-yl)phenol

[0218] Step 1: tert-Butyl (6S, 6aS)-2-(2-hydr oxyphenyl) -6-methyl-5, 6, 6a, 7,9,10-hexahydro-8H-pyrazino[ 1 ', 2 4, 5 ] pyrazino [ 2, 3-c ]pyridazine-8-carboxylate

[0219] To a solution of tert-butyl (6A',6aA')-2-chloro-6-methyl-5,6,6a,7,9, IO-hexahydro-8rt-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (Intermediate 2; 51.5 mg, 0.152 mmol), 2-hydroxyphenylboronic acid (20.9 mg, 0.152 mmol) in 1,4-dioxane (5.0 mL) and water (0.25 mL) was added K3PO4 (96.5 mg, 0.455 mmol). The mixture was bubbled with N2 gas for 5 min, followed by the addition of XPhos Pd G2 (11.9 mg, 15.2 pmol). The mixture was bubbled for another 5 min and stirred at 90 °C for 12 h. The reaction mixture was cooled to rt and concentrated before addition of H2O (3.0 mL). The resulting mixture was extracted with ethyl acetate (3 x 3 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude residue was purified by prep-HPLC on a Cl 8 column (5-60% MeCN / 0.05% formic acid (aq.)) to afford the formate salt of the title compound (60.0 mg, 89.0% yield). LCMS calc, for C21H28N5O3 [M+H]+m / z= 398.2; Found 398.3.

[0220] Step 2: 2-((6S,6aS)-6-Methyl-6,6a, 7,8,9, 10-hexahydro-5H-pyrazino[l',2':4,5]-pyrazin-o[ 2, 3-c ]pyridazin-2-yl)phenol

[0221] To a solution of tert-butyl (65,6a5)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8 / 7-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate formate salt (60.0 mg, 0.135 mmol) in DCM (3.0 mL) was added TFA (1.0 mL). The mixture was stirred at rt for 3 h. The mixture was concentrated and the resulting crude residue containing the TFA salt of the title compound was used without further purification. LCMS calc, for C16H20N5O [M+H]+m / z= 298.2; Found 298.3.

[0222] Step 3: tert-Butyl 4-( ( 6S, 6aS)-2-(2-hydroxyphenyl)-6-methyl-5, 6, 6a, 7, 9,10-hexahydro-8H-pyrazino[ 1 ', 2 4, 5 ]pyrazino[ 2, 3-c ]pyridazin-8-yl)piperidine-l -carboxylate

[0223] To a solution of crude 2-((65,6a5)-6-methyl-6,6a,7,8,9,10-hexahydro-5 / 7-pyrazino-[F,2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol TFA salt in DCE (3.0 mL) and DMSO (1.0 mL) was added A, A-diisopropylethylamine (98 pl, 0.56 mmol), followed by the addition of tertbutyl 4-oxopiperidine-l -carboxylate (75 mg, 0.37 mmol) and sodium triacetoxyboro-hydride (120 mg, 0.56 mmol). The mixture was stirred at rt for 12 h. The crude was purified by prep-HPLC on a C18 column (5-50% MeCN / 0.05% formic acid (aq.)) to afford the formate salt of the title compound (50 mg, 70% yield over 2 steps). LCMS calc, for C26H37N6O3 [M+H]+m / z= 481.3; Found 481.3.

[0224] Step 4: 2-(( 6S, 6aS)-6-Methyl-8-(piperidin-4-yl)-6, 6a, 7, 8, 9, 10-hexahydro-5H-pyrazino-[l',2 4, 5 ]pyrazino[ 2, 3-c ]pyridazin-2-yl)phenol

[0225] To a solution of tert-butyl 4-((65,6a5)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8 / 7-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidine-l -carboxylate (50.0 mg, 0.104 mmol) in DCM (2.0 mL) was added TFA (0.50 mL). The mixture was stirred at rt for 3 h. The reaction mixture was concentrated and the resulting residue containing the TFA salt of the title compound was used in the next step without further purification. LCMS calc, for C21H29N6O [M+H]+m / z= 381.2; Found 381.3.Intermediate 7: 2-((6. S.6:i / ?)-6-Methyl-8-(piperidin-4-yl)-6.6:i.7.8.9.10-hex:ihydro-5 / / - pyrazino [1 ',2': 4,5] pyrazino [2, 3-c] pyridazin-2-yl)phenol

[0226] Step 1: tert-Butyl ( 6S, 6aR)-2-(2-hydroxyphenyl)-6-methyl-5, 6, 6a, 7, 9, 10-hexahydro-8H-pyrazino[ 1 ', 2 4, 5 ]pyrazino[ 2, 3-c ]pyridazine-8-carboxylate\ T The title compound was synthesized by procedures analogous to those outlined in Intermediate 6, Step 1, utilizing Intermediate 3 instead of Intermediate 2. LCMS calc, for C21H28N5O3 [M+H]+m / z= 398.2; Found 398.1.

[0228] Step 2: 2-((6S,6aR)-6-Methyl-6,6a, 7,8,9,10-hexahydro-5H-pyrazino[l',2':4,5]-pyrazino-[ 2, 3-c ]pyridazin-2-yl)phenol

[0229] To a solution of tert-butyl (65,6a7?)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexa- hydro-87 / -pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate formate salt (47.4 mg, 0.107 mmol) in DCM (2.0 mL) was added TFA (0.50 mL). The reaction was stirred at rt for 3 h then concentrated. The crude residue was purified via prep-HPLC on a Cl 8 column (5-50% MeCN / 0.05% formic acid (aq.)) to the formate salt of the title compound. LCMS calc, for C16H20N5O [M+H]+m / z= 298.2; Found 298.1.

[0230] Step 3: tert-Butyl 4-( ( 6S, 6aR)-2-(2-hydroxyphenyl)-6-methyl-5, 6, 6a, 7, 9,10-hexahydro-8H-pyrazino[ 1 ', 2 4, 5 ]pyrazino[ 2, 3-c ]pyridazin-8-yl)piperidine-l -carboxylate

[0231] To a solution of 2-((65',6a7?)-6-methyl-6,6a,7,8,9,10-hexahydro-5J / -pyrazino-[r,2':4,5]-pyrazino[2,3-c]pyridazin-2-yl)phenol formate salt and tert-butyl 4-oxopiperidine-l -carboxylate ( 53.6 mg, 0.269 mmol) in DCE (2.0 mL) and DMSO (1.0 mL) was added 7V,7V-diisopropylethyl- amine (117 pL, 0.673 mmol), followed by sodium triacetoxyborohydride (85.5 mg, 0.404 mmol). The reaction was stirred at rt for 12 h then the reaction mixture was directly purified via prep-HPLC on a C18 column (5-50% MeCN / 0.05% formic acid (aq.)) to afford the formate salt of the title compound (40.0 mg, 71.0% over 2 steps). LCMS calc, for C26H37N6O3 [M+H]+m / z= 481.3; Found 481.2.

[0232] Step 4: 2-((6S,6aR)-6-Methyl-8-(piperidin-4-yl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino-[l',2 4, 5 ]pyrazino[ 2, 3-c ]pyridazin-2-yl)phenol

[0233] The title compound was synthesized by procedures analogous to those outlined in Intermediate 6, Step 4, utilizing 2-((65',6a7?)-6-methyl-6,6a,7,8,9,10-hexahydro-5J / -pyrazino- [l',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol instead of tert-butyl 4-((65,6a5)-2-(2-hydroxy-phenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8J7-pyrazino[r,2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidine-l -carboxylate. LCMS calc, for C21H29N6O [M+H]+m / z= 381.3; Found 381.2.Intermediate 8: 2-((61?,6al?)-6-Methyl-8-(piperidin-4-yl)-6, 6a, 7,8,9, 10-hexahydro-5 / / - pyrazino [1 ',2': 4,5] pyrazino [2, 3-c] pyridazin-2-yl)phenol

[0234] Step 1: tert-Butyl ( 6R, 6aR)-2-(2-hydroxyphenyl)-6-methyl-5, 6, 6a, 7, 9, 10-hexahydro-8H-pyrazino[ 1 2 4, 5 ] pyrazino [ 2, 3-c ]pyridazine-8-carboxylate

[0235] A mixture of tert-butyl (6A,6a7?)-2-chloro-6-methyl-5,6,6a,7,9,10-hexahydro-8JT-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (Intermediate 4; 29.0 mg, 0.0853 mmol), 2-hydroxyphenylboronic acid (35.3 mg, 0.256 mmol), XPhos Pd G2 (6.71 mg, 0.0853 mmol), and K3PO4 (72.5 mg, 0.341 mmol) in 1,4-dioxane (0.83 mL) and water (45 pL) was sparged with N2. The reaction mixture was stirred at 95 °C for 2 h after which the mixture was diluted with EtOAc and water. The layers were separated, and the aqueous phase was extracted with EtOAc (1 x). The combined organic layers were dried with Na2SO4 and concentrated. The crude residue was purified via prep-HPLC (10-30% MeCN / 0.02% formic acid (aq.)). The fractions containing desired product were combined and basified to pH 8 with 5% NaHCOs (aq.), and the acetonitrile was removed under reduced pressure. The resulting aqueous layer was extracted with EtOAc (3 x) and the combined organic layers were dried with Na2SO4 then concentrated to afford the free-base of the title compound (29.0 mg, 79.5%). LCMS calc, for C21H28N5O3 [M+H]+m / z= 398.2; Found 398.1.

[0236] Step 2: 2-((6R,6aR)-6-methyl-6,6a, 7,8,9, 10-hexahydro-5H-pyrazino[ l',2':4,5]-pyrazino-[ 2, 3-c ]pyridazin-2-yl)phenol

[0237] To tert-butyl (6A,6aR)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8JT-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (29.0 mg, 0.0730 mmol) was added HC1 (4.0 M in dioxane; 365 pL, 1.46 mmol). The reaction was stirred at rt for 1 h then concentrated to dryness to give the HC1 salt of the title compound (27.0 mg, 80.4%) as a white solid, which was used without further purification. LCMS calc, for C16H20N5O [M+H]+m / z= 298.2; Found 298.0.

[0238] Step 3: tert-Butyl 4-( ( 6R, 6aR)-2-(2-hydroxyphenyl)-6-methyl-5, 6, 6a, 7, 9,10-hexahydro-8H-pyrazino[ 1 ', 2 4, 5 ]pyrazino[ 2, 3-c ]pyridazin-8-yl)piperidine-l -carboxylate

[0239] 2-((6A,6a7?)-6-methyl-6,6a,7,8,9,10-hexahydro-5J / -pyrazino[r,2':4,5]pyrazino-[2,3-c]pyridazin-2-yl)phenol HC1 salt (27.0 mg, 0.0730 mmol), tert-butyl 4-oxopiperidine-l- carboxylate (72.6 mg, 0.365 mmol), and A, A-diisopropylethylamine (63.5 pL, 0.365 mmol) in DCE (225 pL) were stirred for 30 min before addition of sodium triacetoxyborohydride (23.2 mg, 0.109 mmol). The reaction was stirred at rt overnight then concentrated to dryness. The crude residue was taken up in DMSO and purified via prep-HPLC on a Cl 8 column (10-40% MeCN / 0.02% TFA (aq.)). The fractions containing the desired product were combined and basified to pH 8 with 5% NaHCCh, and the acetonitrile was removed under reduced pressure. The resulting aqueous layer was extracted with EtOAc (3 x), and the combined organic layers were dried with ISfeSCU then concentrated to afford the free-base of the title compound (18.0 mg, 49.9%). LCMS calc, for C26H37N6O3 [M+H]+m / z= 481.3; Found 481.1.

[0240] Step 4: 2-((6R,6aR)-6-Methyl-8-(piperidin-4-yl)-6,6a, 7,8,9, 10-hexahydro-5H-pyrazino[ 1 ', 2 4, 5 ]pyrazino[ 2, 3-c ]pyridazin-2-yl)phenol

[0241] To tert-butyl 4-((6A,6aR)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8JT-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidine-l-carboxylate (18.0 mg, 0.0375 mmol) was added HC1 (4.0 M in dioxane; 190 pL, 0.749 mmol). The reaction was stirred at rt for 1 h then concentrated to dryness to give the HC1 salt of the title compound (17.0 mg, 99.1%) as a white solid. LCMS calc, for C21H29N6O [M+H]+m / z= 381.2; Found 381.2.Intermediate 9: (2. S.4 / ?)-4-(( rt-Biityldiinethylsilyl)oxy)-l-(( / ?)-3-inethyl-2-(3-(2- oxoethoxy)isoxazol-5-yl)butanoyl)-7V-((»S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0242] Step 1: 2-(Trityloxy)ethan-l-ol

[0243] To a round bottom flask was added DCM (700 mL), triethylamine (101 mL, 727 mmol), and ethylene glycol (201 mL, 3600 mmol). The mixture was cooled to 0 °C, and a solution of triphenylchloromethane (100 g, 359 mol) in DCM (300 mL) was added dropwise to maintain the temperature < 5 °C. After the addition was complete, the mixture was warmed to room temperature and stirred overnight. Water (1.5 L) was added to the reaction solution, and the layers were separated. The organic phase was washed with water (3 x 1 L). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated. The crude material was purified by silica column chromatography (20% DCM / hexanes) to afford the title compound (73.3 g, 241 mol, 67.1% yield) as a colorless oil.

[0244] Step 2: Methyl 2-(3-(2-(trityloxy)ethoxy)isoxazol-5-yl)acetate

[0245] To a round bottom flask was added methyl 2-(3-oxo-2,3-dihydroisoxazol-5-yl)acetate (100 g, 637 mmol), 2-(trityloxy)ethan-l-ol (213 g, 700 mmol) and anhydrous THF (1000 mL). The reaction mixture was purged with nitrogen (3x), and then triphenylphosphine (182 g, 694 mmol) was added. The resulting mixture was cooled to -40 °C, and diisopropyl azodi carb oxy late (75.8 mL, 692 mmol) was added dropwise. After the addition, the reaction mixture was stirred overnight at room temperature. The reaction was quenched with sat. NaHCO3(aq.) (2 L), and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 1 L). The combined organic layers were washed with brine (1 L), dried over MgSCh, and concentrated. The crude product was purified by silica gel column chromatography (10-25% EtOAc / hexanes) to afford the title compound (250 g, 560 mmol, 89% yield). 'H-NMR (400 MHz, CDCh) 57.54 - 7.41 (m,6H), 7.37 - 7.19 (m, 9H), 5.97 (d, J= 0.5 Hz, 1H), 4.46 - 4.35 (m, 2H), 3.76 (s, 3H), 3.73 (s, 2H), 3.47 - 3.39 (m, 2H).

[0246] Step 3: Methyl 3-methyl-2-(3-(2-(trityloxy)ethoxy)isoxazol-5-yl)butanoate

[0247] To a round bottom flask was added methyl 2-(3-(2-(trityloxy)ethoxy)isoxazol-5-yl)acetate (300 g, 676 mmol) and anhydrous THF (1.5 L). The reaction mixture was purged with nitrogen (3x). The mixture was cooled to -10 °C, and potassium tert-butoxide (91.2 g, 813 mmol) was added. After stirring for 10 min, isopropyl iodide (74.4 mL, 744 mmol) was added dropwise at 0 to -10 °C. After the addition, the reaction mixture was warmed to room temperature and stirred overnight. The crude solution was directly used for the next step without further workup or purification.

[0248] Step 4: 3-Methyl-2-(3-(2-(trityloxy)ethoxy)isoxazol-5-yl)butanoic acid

[0249] To a crude solution of methyl 3-methyl-2-(3-(2-(trityloxy)ethoxy)isoxazol-5-yl)-butanoate (from Step 2) was added 1.25 NNaOH (aq.) and ethanol (500 mL). The resulting mixture was stirred for 1 h. The reaction mixture was concentrated, and the aqueous phase was adjusted to pH 3-5 with 4 N HC1 (aq.). The solution was extracted with MTBE (3 x 1 L), and the combined organic phases were dried over MgSCU and concentrated. The residue was triturated with ethyl acetate (750 mL) to afford the title compound (227 g, 482 mmol, 71.3% yield over two steps). 'H-NMR (400 MHz, DMSO-d6) 8 12.89 (s, 1H), 7.42 - 7.19 (m, 15H), 6.24 (s, 1H), 4.46 - 4.20 (m, 2H), 3.50 (d, J= 8.7 Hz, 1H), 3.28 - 3.21 (m, 2H), 2.37 - 2.15 (m, 1H), 0.94 (d, J = 6.7 Hz, 3H), 0.83 (d, J= 6.7 Hz, 3H). LC-MS calc. for C29H29NO5Na [M+Na]+m / z= 494.2; Found 494.1.

[0250] Step 5: 2-(3-(2-Hydroxyethoxy)isoxazol-5-yl)-3-methylbutanoic acid

[0251] To a round bottom flask was added 3-methyl-2-(3-(2-(trityloxy)ethoxy)-isoxazol-5-yl)butanoic acid (200 g, 424 mol.), THF (900 mL), and 4 N HC1 (aq.) (500 mL). The reactionmixture was stirred for 4 h. The layers were separated, and the aqueous phase was extracted with MTBE (3 x 600 mL). To the combined organic phases was added 2 N NaOH (aq.) (1.5 L), and the mixture was stirred for 10 min. The layers were separated, and the aqueous layer was extracted with MTBE (2x 500 mL). Then, the aqueous phase was adjusted to pH 1-2 with 2 N HC1 (aq.) and extracted with MTBE (3 x 1 L). The combined organic phases were dried over MgSCU and concentrated to afford the title compound (76 g, 330 mmol, 78% yield) as a white solid. 'H-NMR (400 MHz, DMSO-d6) 8 12.87 (s, 1H), 6.12 (s, 1H), 4.88 (s, 1H), 4.28 - 3.98 (m, 2H), 3.66 (d, J = 3.8 Hz, 2H), 3.48 (d, J = 8.7 Hz, 1H), 2.35 - 2.15 (m, 1H), 0.93 (d, J = 6.7 Hz, 3H), 0.82 (d, J = 6.7 Hz, 3H). LCMS calc. for C10H15NO5Na [M+Na]+m / z= 252.1; Found 252.1.

[0252] Step 6: (2S,4R)-4-((tert-Butyldimethylsdyl)oxy)-l-((R)-2-(3-(2-hydroxyethoxy)-isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-l-( 4-( 4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0253] To a round bottom flask was added HATU (62 g, 160 mmol) and DCM (0.5 L). A solution of 2-(3-(2-hydroxyethoxy)isoxazol-5-yl)-3-methylbutanoic acid (31 g, 140 mmol), (25',4A)-4-((tert-butyldimethylsilyl)oxy)-A-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)-pyrrolidine-2-carboxamide (71.9 g, 162 mmol), and triethylamine (56.3 mL, 404 mmol) in DCM (0.8 L) was added over 15 min. The resulting solution was stirred for 10 min. The reaction was quenched with water (1.2 L), and the layers were separated. The aqueous layer was extracted with DCM (800 mL), and the combined organic layers were concentrated. The crude material was dissolved in MTBE (1 L) and washed with water (1 L) and 5% citric acid (aq.) (3-4 x 1.2 L). The organic layer was then washed with sat. NaHCO3(aq.) (500 mL), concentrated, and purified by SFC to give two diastereomers: “diastereomer A” and the desired “diastereomer B,” which was the title compound (58 g, 88 mmol, 63% yield) as a light yellow oil. 'H-NMR (400 MHz, CDC13) 6 8.67 (s, 1H), 7.50 - 7.32 (m, 5H), 5.92 (d, J= 0.7 Hz, 1H), 5.16 - 4.99 (m, 1H), 4.69 -4.53 (m, 2H), 4.34 (tdd, J= 3.4, 2.7, 0.7 Hz, 2H), 4.01 - 3.88 (m, 2H), 3.74 (dd, J= 10.1, 5.5 Hz, 1H), 3.47 (d, J= 10.0 Hz, 1H), 3.45 - 3.40 (m, 1H), 2.52 (d, J= 0.7 Hz, 3H), 2.47 (d, J= 13.0Hz, 2H), 1.91 - 1.81 (m, 1H), 1.48 (d, J= 6.9 Hz, 3H), 1.03 (d, J= 6.5 Hz, 3H), 0.91 (d, J= 6.7 Hz, 3H), 0.81 (d, J= 0.7 Hz, 9H), 0.04 (d, J= 7.7 Hz, 6H). LC-MS calc. for C33H49N4O6SSi [M+H]+: m / z= 657.3; Found 657.1.

[0254] Step 7. (2S,4R)-4-((tert-Butyldimethylsilyl)oxy)-l-((R)-3-methyl-2-(3-(2-oxoethoxy)isoxazol-5-yl)butanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0255] To a solution of (25',47?)-4-((tert-butyldimethylsilyl)oxy)-l-((7?)-2-(3-(2-hydroxyethoxy)isoxazol-5-yl)-3-methylbutanoyl)-7V-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (1.0 g, 1.5 mmol) in MeCN (20 mL) was added 2-iodoxybezoic acid (0.72 g, 2.6 mmol) and the resulting mixture was heated to 80 °C for 3 h. The reaction mixture was cooled to rt, filtered, and concentrated to afford the title compound (0.96 g, 1.5 mmol, 96% yield) as an off-white solid. LC-MS calc. for C33H47N4O6SSi [M+H]+: m / z= 655.3; Found 655.8.Intermediate 10: Di-tert-butyl ((31?,55)-l-((l?)-3-methyl-2-(3-(2-oxoethoxy)isoxazol-5-yl)butanoyl)-5-(((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl) phosphateyl)phenyl)ethyl)carbamoyl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-yl)isoxazol-3-yl)oxy)ethyl acetate

[0257] To a solution of (25',47?)-4-((terLbutyldimethylsilyl)oxy)-l-((7?)-2-(3-(2-hydroxyethoxy)isoxazol-5-yl)-3-methylbutanoyl)-7V-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (500 mg, 0.761 mmol, Intermediate 9, Step 6) and TEA (0.318 mL, 2.28 mmol) in DCM (10.0 mL) was added acetyl chloride (0.135 mL, 1.90 mmol). The resulting mixture was stirred for 24 h. The reaction mixture was diluted with water (10 mL), the two phases were separated, and the aqueous phase was extracted with DCM (3 x 5.0 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude residue was dissolved in THF (5.0 mL) then TBAF solution (0.761 mL, 0.791mmol, IM in THF) was added. The reaction was stirred at rt for 1 h. The reaction mixture was concentrated and purified by silica gel chromatography (0-7% MeOH / DCM) to afford the title compound (350 mg, 0.599 mmol, 78.6% yield) as a colorless solid. LCMS calc, for C29H37N4O7S [M+H]+: m / z = 585.2; Found: 585.1.

[0258] Step 2: 2-((5-((R)-l-((2S,4R)-4-((Di-tert-butoxyphosphoryl)oxy)-2-(((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-yl)isoxazol-3 -yl) oxy) ethyl acetate

[0259] To a solution of 2-((5-((A)-l-((25,4A)-4-hydroxy-2-(((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-yl)isoxazol-3-yl)oxy)ethyl acetate (258 mg, 0.441 mmol) and 17 / -tetrazole (4.90 mL, 2.21 mmol, 0.45 M in MeCN) in THF (5.0 mL) was added di- / c / 7-butyl diisopropylphosphoramidite (0.557 mL, 1.77 mmol). The reaction was stirred for 24 h before addition of more 17 / -tetrazole (4.90 mL, 2.21 mmol, 0.45 M in MeCN) and di-tert-butyl diisopropylphosphoramidite (0.557 mL, 1.77 mmol). The reaction was stirred a further 8 h before addition of more 17 / -tetrazole (4.90 mL, 2.21 mmol, 0.45 M in MeCN) and di-tert-butyl diisopropylphosphoramidite (0.557 mL, 1.77 mmol). The reaction mixture was stirred for 16 h then concentrated before being partitioned between sat. NaHCCh (aq.) (10.0 mL) and DCM (10.0 mL). The two phases were separated and the aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude residue was used directly in the next step without further purification. LCMS calc, for C37H54N4O10PS [M+H]+: m / z = 777.3; Found: 777.4.

[0260] Step 3: Di-tert-butyl ( 3R, 5S)-l-( (R)-2-( 3-(2-hydroxyethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-( (S)-l-( 4-( 4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl) phosphate

[0261] To a solution 2-((5-(( / ?)-l-((25',4 / ?)-4-((di-terLbutoxyphosphoryl)oxy)-2-(((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-yl)isoxazol- 3-yl)oxy)ethyl acetate (343 mg, 0.441 mmol) in MeOH (3.0 mL) was added potassium carbonate (183 mg, 1.32 mol) at 0 °C. The reaction mixture was warmed to rt and stirred for 5 min. The mixture was filtered before being diluted with sat. NH4CI (aq.) (10 mL) and DCM (10 mL). The two phases were separated and the aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-8% MeOH / DCM) to afford the title compound (200 mg, 0.272 mmol, 61.7% yield) as a yellow solid. LCMS calc, for C35H52N4O9PS [M+H]+: m / z = 735.3; Found: 735.5.

[0262] Step 4. Di-tert-butyl ( ( 3R, 5S)-l-(R)-3-methyl-2-( 3-(2-oxoethoxy)isoxazol-5-yl)butanoyl)-5-(((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl) phosphate

[0263] To a suspension of di- / c / 7-butyl ((37?,55)-l-((7?)-2-(3-(2-hydroxyethoxy)-isoxazol-5-yl)- 3-methylbutanoyl)-5-(((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)-pyrrolidin-3-yl) phosphate (1.0 g, 1.4 mmol) andNaHCO3(0.46 g, 5.4 mmol) in DCM (11 mL) was added Dess-Martin Periodinane (1.2 g, 2.7 mmol). The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with DCM (50 mL), sat. NaHCO3(aq.) (10 mL) and sat. Na2S20s (aq.) (10 mL). The resulting two phases were separated, and the aqueous layer was extracted with DCM (50 mL). The combined organic layer was dried over solidum sulfate, filtered, and concentrated to afford the title compound (810 mg, 1.1 mmol, 80% yield) which was used without further purification. LCMS calc, for C35H50N4O9PS [M-CsHie]: m / z = 621.6; Found: 621.5.Intermediate 11: ( )-2-Fluoro-6-(8-(piperidin-4-ylmethyl)-6, 6a, 7,8,9, 10-hexahydro-5Z7- pyrazino [1 ’,2’: 4,5] pyrazino [2,3-c] pyridazin-2-yl)phenol

[0264] Step 1. tert-Butyl (S)-4-((2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[ 1 2 4, 5 ] pyrazino [ 2, 3-c ]pyridazin-8-yl)methyl)piperidine-l-carboxylate

[0265] The title compound was prepared using procedures analogous to those used to synthesize Intermediate 6, Step 3, utilizing ( / )-2-fluoro-6-(6,6a,7,8,9, IO-hexahydro-5rt-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol, which can be prepared as described in WO2023220577 (Intermediate 1), and tert-butyl 4-formylpiperidine-l -carboxylate instead of2- ((6, S',6aA')-6-methyl-6,6a,7,8,9, l0-hexahydro-57 / -pyrazino-[l',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol and tert-butyl 4-oxopiperidine-l -carboxylate, respectively. LCMS calc, for C26H36FN6O3 [M+H]+m / z= 499.3; Found: 499.1.

[0266] Step 2. (S)-2-Fluoro-6-(8-(piperidin-4-ylmethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[ 1 2 4, 5 ]pyrazino[ 2, 3-c ]pyridazin-2-yl)phenol

[0267] The title compound was prepared using procedures analogous to those used to synthesize Intermediate 6, Step 4, utilizing tert-butyl fS')-4-((2-(3-fluoro-2-hydroxyphenyl)- 5,6,6a,7,9,10-hexahydro-8J / -pyrazino[r,2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidine- 1 -carboxylate instead of tert-butyl 4-((65,6a5)-2-(2-hydroxy-phenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8J / -pyrazino[r,2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidine-l -carboxylate. LCMS calc, for C21H28FN6O [M+H]+m / z= 399.2; Found: 399.1.

[0268] Intermediate 12: (5)-2-(6a-Ethyl-8-(piperidin-4-yl)-6,6a,7,8,9,10-hexahydro-5Z7- pyrazino [1 ',2': 4,5] pyrazino [2, 3-c] pyridazin-2-yl)phenol

[0269] Step 1. tert-Butyl (R)-6a-ethyl-2-(2-hydroxyphenyl)-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[ 1 ', 2 4, 5 ]pyrazino[ 2, 3-c ]pyridazine-8-carboxylate

[0270] To a solution of di-tert-butyl ( / )-2-chloro-6a-ethyl-6-oxo-6a,7,9, IO-tetrahydro-5rt-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazine-5,8(6rt)-dicarboxylate (0.500 g, 1.07 mmol), which can be prepared as described in WO2023220577 (Intermediate 40, Step 5, Isomer 2), cesium carbonate (0.697 g, 2.14 mmol), and 2-hydroxyphenylboronic acid (0.295 g, 2.14 mmol) in 1,4- dioxane (10 mL) and water (1.0 mL) was added XPhos Pd G2 (0.168 g, 0.210 mmol). The mixture was sparged with N2 for 5 min and then heated to 80 °C for 3 h. The reaction mixture was cooled to rt and diluted with EtOAc (20 mL) and water (20 mL). The resulting two phases were separated, and the aqueous layer was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-60% EtOAc / hexanes) to afford the title compound (0.504 g, >99% yield) as a tan solid. LCMS calc, for C22H28N5O4 [M+H]+m / z= 426.2; Found: 426.1.

[0271] Step 2. tert-Butyl (S)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a, 7,9, 10-hexahydro-8H-pyrazino[ 1 ', 2 4, 5 ]pyrazino[ 2, 3-c ]pyridazine-8-carboxylate

[0272] To a solution of tert-butyl (A)-6a-ethyl-2-(2-hydroxyphenyl)-6-oxo-5,6,6a,7,9,10-hexahydro-8J / -pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (0.504 g, 1.18 mmol) in THF (6.5 mL) was added borane dimethylsulfide complex (4.7 mL, 9.40 mmol, 2.0 M in THF). The reaction mixture was stirred at 60 °C for 1.5 h then cooled to rt, diluted with MeOH, and concentrated. The residue was dissolved in EtOH (10 mL), and then acetic acid (1.34 mL, 23.5 mmol) and sodium cyanoborohydride (0.369 g, 5.88 mmol) were added. The reaction mixture was stirred at 80 °C overnight. The mixture was cooled to rt, diluted with sat. NaHCO3(aq.), and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude residue was purifiedby silica gel chromatography (0-20% MeOH / DCM) to afford the title compound (0.558 g, >99% yield) as a tan solid. LCMS calc, for C22H30N5O3 [M+H]+m / z= 412.2; Found: 412.1.

[0273] Step 3. (R)-2-(6a-Ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[r,2':4,5]-pyrazino[2,3-c ]pyridazin-2-yl)phenol

[0274] The title compound was prepared using procedures analogous to those used in Intermediate 8, Step 2, utilizing tert-butyl (5)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8J / -pyrazino[r,2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate instead of tert-butyl (67?,6a7?)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8JT-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate. LCMS calc. for C17H22N5O [M+H]+m / z= 312.2; Found: 312.1.

[0275] Step 4. (S)-2-(6a-Ethyl-8-(piperidin-4-yl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino-[l',2 4, 5 ]pyrazino[ 2, 3-c ]pyridazin-2-yl)phenol

[0276] The title compound was prepared using procedures analogous to those used to synthesize Intermediate 5, Step 2, utilizing (7?)-2-(6a-ethyl-6,6a,7,8,9,10-hexahydro-5JT-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol instead of 2-((67?,6a5)-6-methyl-6,6a,7,8,9,10-hexahydro-5J / -pyrazino-[r,2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol. LCMS calc, for C22H31N6O [M+H]+m / z= 395.3; Found: 395.4.Compound I: (25',41?)-4-Hydroxy-l-((l?)-2-(3-(2-(4-((65',6a5)-2-(2-hydroxyphenyl)-6-methyl- 5.6.6a.7.9.10-hex:ihydro-8 / / -pyr:izino| r.2':4.5|pyr:izin()|2.3-c|pyiid:izin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-7V-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0277] Step 1: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-l-((R)-2-(3-(2-(4-((6S,6aS)-2-(2-hydroxyphenyl)-6-methyl-5, 6, 6a, 7, 9, 10-hexahydro-8H-pyrazino[ 1 ', 2 ':4,5]pyrazino[2, 3-c ]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-( (S)-l-( 4-( 4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0278] To a solution of 2-((65,6a5)-6-methyl-8-(piperidin-4-yl)-6,6a,7,8,9, 10-hexahydro-5Z7-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol TFA salt (Intermediate 6; 30.0 mg, 0.0493 mmol) in DMF (2.0 mL) and water (0.10 mL) was added NaHCCh (25.5 mg, 0.197 mmol), followed by (25,4A)-4-((terLbutyldimethylsilyl)oxy)-l-((A)-3-methyl-2-(3-(2-oxo- ethoxy)isoxazol-5-yl)butanoyl)-7V-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide (Intermediate 9; 51.6 mg, 0.0788 mmol) and sodium triacetoxyborohydride (33.4 mg, 0.158 mmol). The mixture was stirred at rt for 12 h then purified by prep-HPLC on a C18 column (5-50% MeCN / 0.05% formic acid (aq.)) to afford the formate salt of the title compound (50.0 mg, 95.2% yield). LCMS calc, for C₅₄H₇₅N₁₀O₆SiS [M+H]+m / z= 1019.5; Found 1019.5.

[0279] Step 2: (2S,4R)-4-Hydroxy-l-((R)-2-(3-(2-(4-((6S,6aS)-2-(2-hydroxyphenyl)-6-methyl-5, 6, 6a, 7, 9, 10-hexahydro-8H-pyrazino[ 1 ', 2 4, 5 ]pyrazino[ 2, 3-c ]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-( (S)-l-( 4-( 4-methylthiazol-5-yl)phenyl)ethyl)~ pyrrolidine-2-carboxamide

[0280] To a solution of (25',4A)-4-((terLbutyldimethylsilyl)oxy)-l-((A)-2-(3-(2-(4-((65',6a5)-2- (2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8J / -pyrazino[r,2':4,5]-pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-7V-((5)-l-(4-(4-methyl-thiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide formate salt (50.0 mg, 0.0469 mmol) in THF (1.0 mL) and IPA (1.0 mL) was added cone. HC1 (aq.) (0.50 mL). The mixture was stirred at rt for 15 min then the crude mixture was purified by prep-HPLC on a Cl 8 column (5- 50% MeCN / 0.05% formic acid (aq.)) to afford the formate salt of the title compound (32.9 mg, 73.8% yield). LCMS calc, for C₄₈H₆₁N₁₀O₆S [M+H]+m / z= 905.4; Found 905.4.

[0281] The HC1 salt of the title compound can be prepared by treating the combined fractions containing the formate salt of title compound from the prep-HPLC purification with HC1, followed by lyophilization.

[0282] The free-base of title compound was obtained by the following procedure: To a solution of the HC1 salt of the title compound in DCM and water (1:1) was added NaHCO3until a pH of 7 was obtained. The organic layer was separated, and the aqueous layer was extracted with DCM (2 x). The combined organic layers were dried with Na2SO4 then concentrated to afford the title compound as its free-base. 'H NMR (400 MHz, CDC13) 88.67 (s, 1H), 7.56 (d, J= 7.6 Hz, 1H), 7.45 (d, J= 7.9 Hz, 1H), 7.40 (d, J= 8.9 Hz, 2H), 7.36 (d, J= 8.3 Hz, 2H), 7.24 (m, 1H), 7.01 (d, J= 8.3 Hz, 1H), 6.90 - 6.84 (m, 2H), 5.94 (s, 1H), 5.69 (br s, 1H), 5.51 (m, 1H), 4.70 - 4.58 (m, 2H), 4.42 (m, 2H), 3.77 (dd, J= 10.8, 5.3 Hz, 1H), 3.70 (m, 2H), 3.61 (dd, J= 10.7, 2.8 Hz, 1H), 3.50 (m, 1H), 3.46 (m, 1H), 3.18 (m, 4H), 3.10 -2.86 (m, 5H), 2.53 (s, 3H), 2.55 - 2.37 (m, 4H), 2.34-2.15 (m, 2H), 2.13 - 1.94 (m, 2H), 1.92 - 1.66 (m, 4H), 1.49 (d, J= 7.4 Hz, 3H), 1.31 (d, J = 6.0 Hz, 3H), 1.04 (d, J= 6.4 Hz, 3H), 0.92 (d, J= 6.4 Hz, 3H).Compound II: (25',47?)-4-Hydroxy-l-((l?)-2-(3-(2-(4-((61?,6a5)-2-(2-hydroxyphenyl)-6-inethyl-5.6.6a.7.9.10-hexahydro-8 / / -pyr:izino| r.2':4.5|pyr:izino|2.3-c|pyiidazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-A-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0283] To a solution of 2-((6A,6a5)-6-methyl-8-(piperidin-4-yl)-6,6a,7,8,9, lO-hexahydro-5 / 7-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol TFA salt (Intermediate 5; 15.7 mg, 0.0188 mmol) and (25',47?)-4-((terLbutyldimethylsilyl)oxy)-l-((7?)-3-methyl-2-(3-(2-oxo-ethoxy)isoxazol-5-yl)butanoyl)-7V-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Intermediate 9; 12.3 mg, 0.0188 mmol) in DMF (1.0 mL) and water (50 pL) was added NaHCCh (6.31 mg, 0.0751 mmol) and sodium triacetoxyborohydride (7.95 mg, 0.0375 mmol). The mixture was stirred at rt for 1 h then purified via prep-HPLC on a C18 column (10-40% MeCN / 0.05% TFA (aq.)). The combined fractions containing the desired product were concentrated to ~10 mL then treated with 0.1 mL TFA and lyophilized to give a crude residue which was purified via prep-HPLC on a C18 column (10-40% MeCN / 0.05% TFA (aq.)) to give the TFA salt of the title compound (6.50 mg, 34.0%) as a colorless solid. LC-MS calc, for C₄₈H₆₁N₁₀O₆S [M+H]+: m / z= 905.4; Found 905.4.Compound III: (25',47?)-4-Hydroxy-l-((l?)-2-(3-(2-(4-((61?,6al?)-2-(2-hydroxyphenyl)-6-inethyl-5.6.6a.7.9.10-hex:ihydro-8 / / -pyr:izino| r.2':4.5|pyr:izino|2.3-c|pyiid:izin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0284] Step 1: (2S,4R)-4-((tert-Butyldimethylsilyl)oxy)-l-((R)-2-(3-(2-(4-((6R,6aR)-2-(2-hydroxyphenyl)-6-methyl-5, 6, 6a, 7, 9, 10-hexahydro-8H-pyrazino[ 1 2 ':4,5]pyrazino[2, 3-c ]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-( (S)-l-( 4-( 4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0285] A mixture of tert-butyl 4-((6A,6a7?)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexa-hydro-S / f-pyrazinofr^'A^JpyrazinoP^-clpyridazin-S-y^piperidine-l -carboxylate HC1 salt (Intermediate 8; 16.0 mg, 0.0353 mmol), (25,4A)-4-((tert-butyldimethylsilyl)oxy)-l-((A)-3-methyl-2-(3-(2-oxoethoxy)isoxazol-5-yl)butanoyl)-A-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)-ethyl)pyrrolidine-2-carboxamide (Intermediate 9; 21.0 mg, 0.0321 mmol), and NaHCOs (6.73 mg, 0.0802 mmol) in DMF (180 pL) and water (10 pL) was stirred at rt for 1 h then treated with sodium triacetoxyborohydride (13.6 mg, 0.0641 mmol), portion-wise, over 10 min. The reaction was stirred for 2 h then diluted with DMSO and water and purified via prep-HPLC on a Cl 8 column (15-30% MeCN / 0.02% formic acid (aq.)). The fractions containing the desired product were combined and basified to pH 8 with 5% NaHCCh (aq.) and the acetonitrile was removed under reduced pressure. The resulting aqueous layer was extracted with EtOAc (3 x) and the combined organic layers were dried with Na2SC>4 then concentrated to afford the free-base of the title compound (12.0 mg, 36.7%). LCMS calc, for C₅₄H₇₅N₁₀O₆SSi [M+H]+m / z= 1019.5; Found 1019.5.

[0286] Step 2: (2S,4R)-4-Hydroxy-l-((R)-2-(3-(2-(4-((6R,6aR)-2-(2-hydroxyphenyl)-6-methyl-5, 6, 6a, 7, 9, 10-hexahydro-8H-pyrazino[ 1 2 4, 5 ]pyrazino[ 2, 3-c ]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-( (S)-l-( 4-( 4-methylthiazol-5-yl)phenyl)ethyl)~ pyrrolidine-2-carboxamide

[0287] To a solution of (2k,4 / )-4-(( / c77-butyldimethylsilyl)oxy)-l-(( / )-2-(3-(2-(4-((6 / ,6a / )-2- (2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8J / -pyrazino[r,2':4,5]-pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-7V-((5)-l-(4-(4-methyl-thiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (6.00 mg, 0.0589 mmol) in MeOH (50 pL) was added HC1 (4.0 M in dioxane; 15 pL, 58.9 pmol). The mixture was stirred at rt for 30 min then was concentrated, taken up in DMSO, and purified via prep-HPLC on a Cl 8 column (15- 30% MeCN / 0.02% formic acid (aq.)). Fractions containing the desired product were combined and concentrated, then treated with 0.1% TFA (aq.) and lyophilized to give the TFA salt of the title compound (2.90 mg, 53.8%). LCMS calc, for C₄₈H₆₁N₁₀O₆S [M+H]+m / z= 905.4; Found 905.5.Compound IV: (2»S,41?)-4-Hydroxy-l-((l?)-2-(3-(2-(4-((6»S,6al?)-2-(2-hydroxyphenyl)-6- inetliyl-5.6.6:i.7.9.10-liex:ihydro-8 / / -pyr:izino| l'.2':4.5|pyr:izino|2.3-c|pyiidazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-A-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0288] The title compound was synthesized by procedures analogous to those outlined in Compound I, Steps 1-2, utilizing 2-((65,6aR)-6-methyl-8-(piperidin-4-yl)-6,6a,7,8,9,10-hexahydro-5J / -pyrazino[T,2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (Intermediate 7) instead of 2-((65',6aS)-6-methyl-8-(piperidin-4-yl)-6,6a,7,8,9,10-hexahydro-5J / -pyrazino[T,2':4,5]-pyrazino[2,3-c]pyridazin-2-yl)phenol (Intermediate 6). LCMS calc, for C48H6iNioOeS [M+H]+m / z= 905.4; Found 905.4.Compound V: (3R,5S)-l-((R)-2-(3-(2-(4-((6S,6aS)-2-(2-hydroxyphenyl)-6-methyl- 5,6,6a,7,9,10-hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)- carbamoyl)pyrrolidin-3-yl dihydrogen phosphate

[0289] Step 1: ( 6S, 6aS)-2-Chloro-6-methyl-6, 6a, 7, 8, 9, 10-hexahydro-5H-pyrazino[ 1 2 ':4,5]~ pyrazino[ 2, 3-c Jpyridazine

[0290] tert-Butyl (65,6a5)-2-chloro-6-methyl-5,6,6a,7,9, 10-hexahydro-8J / -pyrazino[l',2':4,5]-pyrazino[2,3-c]pyridazine-8-carboxylate (50.0 mg, 0.147 mmol, Intermediate 2) was dissolved in HC1 solution (3.00 mL, 12.0 mmol, 4N in 1,4-di oxane) and the mixture was stirred for 3 h. The reaction mixture was concentrated and used in the next step without further purification. LCMS calc, for C₁₀H₁₅ClN₅ [M+H]+: m / z = 240.1; Found: 240.1.

[0291] Step 2: tert-Butyl 4-( ( 6S, 6aS)-2-chloro-6-methyl-5, 6, 6a, 7, 9, 10-hexahydro-8H-pyrazino-[l',2 4, 5 ]pyrazino[ 2, 3-c ]pyridazin-8-yl)piperidine-l -carboxylateTo a solution of (65,6aS)-2-chloro-6-methyl-6,6a,7,8,9,10-hexahydro-5J / -pyrazino[l',2':4,5]-pyrazino[2,3-c]pyridazine (2.6 g, 11 mmol) in DCE (54 mL) was added DIPEA (9.3 mL, 54 mmol), tert-butyl 4-oxopiperidine-l -carboxylate (2.8 g, 14 mmol), and sodium triacetoxyboro-hydride (6.8 g, 32 mmol). The reaction mixture was stirred for 12 h. The mixture was diluted with water (20 mL) and extracted with DCM (30 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was suspended in 10% v / v EtOAc / heptane and stirred vigorously for 15 min. The solid was collected by filtration to afford the title compound (4.2 g, 10 mmol, 93% yield). LCMS calc, for C20H32CIN6O2 [M+H]+: m / z = 423.2; Found: 423.2.Step 3. tert-Butyl 4-((6S,6aS)-2-(2-(methoxymethoxy)phenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[ I 2 4, 5 ]pyrazino[ 2, 3-c ]pyridazin-8-yl)piperidine-l -carboxylateTo a solution of tert-butyl 4-((65,6a5)-2-chloro-6-methyl-5,6,6a,7,9,10-hexahydro-8J / -pyrazino-[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidine-l-carboxylate (8.0 g, 19 mmol), (2-(methoxy-methoxy)phenyl)boronic acid (6.9 g, 37 mmol), and K3PO4 (12 g, 57 mmol) in 1,4-dioxane (80 mL) and water (27 mL) was added XPhos Pd G3 (0.76 g, 0.95 mmol). The resulting mixture wasdegassed with N2 and heated to 100 °C for 40 min. The reaction mixture cooled rt, concentrated to remove the 1,4-dioxane, and residual mixture was extracted with DCM (30 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (0-20% MeOH / DCM) to afford the title compound (6.3 g, 12 mmol, 63% yield). LCMS calc, for C28H41N6O4 [M+H]+: m / z = 525.3; Found: 525.7.

[0292] Step 4. (6S,6aS)-2-(2-(Methoxymethoxy)phenyl)-6-methyl-8-(piperidin-4-yl)- 6, 6a, 7, 8, 9, 10-hexahydro-5H-pyrazino[ 1 ', 2 4, 5 ]pyrazino[ 2,3-c JpyridazineTo a solution of tert-butyl 4-((65,6a5)-2-(2-(methoxymethoxy)phenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8JH-pyrazino[T,2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidine-l -carboxylate

[0293] (3.0 g, 7.1 mmol) and 2,6-lutidine (2.7 g, 25 mmol) in DCM (45 mL) was added TMSOTf (5.4 g, 24 mmol) dropwise at 0 °C. The reaction was warmed to 30 °C and stirred for 1 h before being diluted with MeOH (30 mL). The reaction mixture was concentrated to remove excess solvent and the resulting solution containing the desired product was used in the next step without further purification. LCMS calc, for C23H33N6O2 [M+H]+: m / z = 425.3; Found: 425.7.

[0294] Step 5. Di-tert-butyl ((3R,5S)-l-((R)-2-(3-(2-(4-((6S,6aS)-2-(2-(methoxymethoxy)~ phenyl)-6-methyl-5, 6, 6a, 7, 9, 10-hexahydro-8H-pyrazino[ 1 ', 2 ':4,5]pyrazino[2, 3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-l-(4-(4-methylthiazol-5-

[0295] To a suspension of crude (65,6a5)-2-(2-(methoxymethoxy)phenyl)-6-methyl-8-(piperidin-4-yl)-6,6a,7,8,9,10-hexahydro-5J / -pyrazino[r,2':4,5]pyrazino[2,3-c]pyridazine, ditert-butyl ((3R, 55)- 1 -((7?) -3 -methyl-2-(3 -(2-oxoethoxy)i soxazol -5 -yl)butanoyl)-5 -(((5)- 1 -(4 -(4 -methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl) phosphate (6.1 g, 8.3 mmol, Intermediate 10), and NaHCCh (2.9 g, 35 mmol) in DMF (180 mL) and water (18 mL) was added sodium triacetoxyborohydride (1.9 g, 9.0 mmol). The reaction mixture was stirred for 5 h before being poured into water (1.8 L) and extracted with DCM (90 mL x 2). The combined organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The crude oil was purified by silica gel chromatography (100% EtOAc then 3-10% MeOH / DCM) to afford the title compound (3.7 g, 3.2 mmol, 46% yield over two steps) as a yellow foam solid. LCMS calc, for C₅₈H₈₂N₁₀O₁₀PS [M+H]+: m / z = 1141.6; Found: 1142.1.

[0296] Step 6. (3R,5S)-l-((R)-2-(3-(2-(4-((6S,6aS)-2-(2-Hydroxyphenyl)-6-methyl- 5, 6, 6a, 7, 9, 10-hexahydro-8H-pyrazino[ 1 ', 2 4, 5 ]pyrazino[ 2, 3-c ]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)~ carbamoyl)pyrrolidin-3-yl dihydrogen phosphate

[0297] To a solution of i-tert-butyl ((3R,5S)-l-((R)-2-(3-(2-(4-((6S,6aS)-2-(2-(methoxy-methoxy)phenyl)-6-methyl-5, 6, 6a, 7, 9, 10-hexahydro-8H-pyrazino[ 1 ', 2 ':4,5]pyrazino[2, 3-c ]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-( (S)-l-( 4-( 4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl) phosphate (150 mg, 0.13 mmol) in IPA (0.50 mL) was added a solution of cone. HC1 (0.50 mL, 0.13 mmol) dropwise at 0 °C. The reaction mixture was warmed to rt and stirred for 15 min before being directly purified by prep-HPLC on a C18 column (10-30% MeCN / 0.05% formic acid (aq.)) to afford the formate salt of the title compound (110 mg, 0.10 mmol, 78% yield), as a white solid.JH NMR (400 MHz, DMSO-tL) 8 8.98 (s, 1H), 8.43 (d, J= 7.5 Hz, 1H), 8.14 (s, 1H), 7.84 (d, J= 7.9 Hz, 1H), 7.50 (bs, 1H), 7.43 (d, J= 8.3 Hz, 2H), 7.37 (d, J= 8.2 Hz, 2H), 7.28 - 7.18 (m, 2H), 6.93 - 6.80 (m, 2H), 6.14 (s, 1H), 6.02 (s, 0.1H, minor rotamer), 4.98 - 4.86 (m, 1H), 4.70 - 4.61 (m, 1H), 4.58 - 4.40 (m, 2H), 4.38 - 4.29 (m, 1H), 4.16 - 4.04 (m, 1H), 3.76 (d, J= 11.0 Hz, 1H), 3.67 (d, J = 9.5 Hz, 2H), 3.53 - 3.26 (m, 5H), 3.13 (d, J= 10.7 Hz, 1H), 3.04 (d, J= 10.6 Hz, 1H), 2.98 -2.86 (m, 2H), 2.86 - 2.71 (m, 2H), 2.64 - 2.53 (m, 1H), 2.45 (s, 3H), 2.41 - 2.14 (m, 4H), 2.12 - 1.98 (m, 1H), 1.98 - 1.78 (m, 4H), 1.46 (d, J= 6.9 Hz, 0.3H, minor rotamer), 1.39 (d, J= 6.9 Hz, 3H), 1.23 (d, J= 6.1 Hz, 3H), 0.96 (d, J= 6.5 Hz, 3H), 0.81 (d, J= 6.7 Hz, 3H). LCMS calc, for C48H62N10O9PS [M+H]+m / z= 985.4; Found 985.7.Compound VI. (2-((65,6a5)-8-(l-(2-((5-((l?)-l-((25',41?)-4-Hydroxy-2-(((5)-l-(4-(4-methyl-thiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-yl)isoxazol-3-yl )oxy )et hyl)piperidin-4-yl)-6-met hyl-6.6a.7.8.9.10-hexahydro-5 / / -py razino 11 '.2': 4,5] - pyrazino [2,3-c] pyridazin-2-yl)phenoxy)methyl dihydrogen phosphate

[0298] Step 1. (2-Bromophenoxy)methyl di-tert-butyl phosphate

[0299] Di(tert-butyl) chloromethyl phosphate (0.97 g, 3.8 mmol) was added to a solution of 2-bromophenol (0.50 g, 2.9 mmol), potassium carbonate (1.2 g, 8.7 mmol), and sodium iodide (43 mg, 0.29 mmol) in DMF (12 mL) at 0 °C. The reaction mixture was warmed to rt and stirred for 72 h. The mixture was diluted with water (15 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by prep-HPLC on a Cl 8 column (0-60% MeCN / 0.05% TFA (aq.)). The collected fractions were neutralized with sat. NaHCO3(aq.), concentrated to remove the MeCN, and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the title compound (1.1 g, 2.8 mmol, 97% yield). LCMS calc, for C15H25BrO5P [M+H]+: m / z = 395.1; Found: 395.4.

[0300] Step 2. tert-Butyl 4-(( 6S, 6aS)-2-(2-( ( tert-butoxy(hydroxy)phosphoryl)oxy) -methoxy) -phenyl) -6-methyl-5, 6, 6a, 7, 9, 10-hexahydro-8H-pyrazino[ 1 2 ':4,5]pyrazino[2, 3-c]pyridazin-8-yl)piperidine-l -carboxylate

[0301] To a mixture of (2-bromophenoxy)methyl di-tert-butyl phosphate (1.0 g, 2.5 mmol), potassium trimethylacetate (0.71 g, 5.1 mmol), and tetrahydroxydiboron (0.698 g, 7.6 mmol) in IPA (50 mL) was added XPhos Pd G2 (40 mg, 51 pmol) and XPhos (48 mg, 100 pmol). The mixture was degassed with N2 then heated to 75 °C for 1 h. The reaction mixture was cooled to rt and filtered before addition of tert-butyl 4-((65,6a5)-2-chloro-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidine-1-carboxylate (1.1 g, 2.5 mmol, Compound V, Step 2), XPhos Pd G2 (40 mg, 51 pmol), and potassium phosphate tribasic (1.6 g, 7.6 mmol). The resulting mixture was heated to 80 °C for 2 h. The reaction mixture was cooled to rt and concentrated. The residue was dissolved in water (20 mL) and extracted with CHCI3TPA (3: 1 v / v) (30 mL x 5). The combined organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by prep-HPLC on a C18 column (5-40% MeCN / 0.05% TFA (aq.)) to afford the title compound (0.38 g, 0.59 mmol, 23% yield) as a white solid. LCMS calc, for C31H48N6O7P [M+H]+: m / z = 647.3; Found: 647.7.

[0302] Step 3. (2-((6S,6aS)-6-Methyl-8-(piperidin-4-yl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino-[l',2 4, 5 ]pyrazino[ 2, 3-c ]pyridazin-2-yl)phenoxy)methyl dihydrogen phosphate

[0303] A solution of 6N HC1 (aq.) (3.0 mL, 18 mmol) was added to tert-butyl 4-((65,6aS)-2-(2-(((tert-butoxy(hydroxy)phosphoryl)oxy)methoxy)phenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidine-1-carboxylate (0.38 g, 0.59 mmol) and the resulting mixture was stirred at rt for 15 min. The reaction mixture was purified directly by prep-HPLC on a C18 column (5-35% MeCN / 0.05% TFA (aq.)) to afford the TFA salt of thetitle compound (0.27 g, 0.45 mmol, 76% yield) as a white solid. LCMS calc, for C22H32N6O5P [M+H]+: m / z = 491.2; Found: 491.6.

[0304] Step 4. (2-((6S,6aS)-8-(l-(2-((5-((R)-l-((2S,4R)-4-((tert-Butyldimethylsilyl)-oxy)-2- ( ( (S)-l-( 4-( 4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-yl)isoxazol-3-yl)oxy)ethyl)piperidin-4-yl)-6-methyl-6, 6a, 7,8,9, 10-hexahydro-5H-pyrazin-o[l',2 4, 5 ]pyrazino[ 2, 3-c ]pyridazin-2-yl)phenoxy)methyl dihydrogen phosphate

[0305] To a solution of crude (2, S',4 / )-4-(( / c / 7-butyldimethylsilyl)oxy)- l-(( / )-3-methyl-2-(3-(2-oxoethoxy)isoxazol-5-yl)butanoyl)-A-((5)-l-(4-(4-methylthiazol-5-yl)phenyl)-ethyl)pyrrolidine-2-carboxamide (15 mg, 31 pmol, Intermediate 9) in DMSO (0.80 mL) was added DIPEA (53 pL, 0.31 mmol), (2-((65,6a5)-6-methyl-8-(piperidin-4-yl)-6,6a,7,8,9, 10-hexahydro-5Z7-pyrazino- [l',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenoxy)methyl dihydrogen phosphate (30 mg, 46 pmol), and sodium triacetoxyborohydride (19 mg, 92 pmol). The resulting mixture was stirred at 50 °C for 30 min. The reaction mixture was cooled to rt and purified directly by prep-HPLC on a C18 column (5-45% MeCN / 0.05% TFA (aq.)) to afford the TFA salt of the title compound (26 mg, 21 pmol, 68% yield) as a white solid. LCMS calc, for C55H78N10O10PSSi [M+H]+: m / z = 1129.5; Found: 1129.9.

[0306] Step 5. (2-((6S,6aS)-8-(l-(2-((5-((R)-l-((2S,4R)-4-Hydroxy-2-(((S)-l-(4-(4-methyl-thiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-yl)isoxazol-3-yl)oxy)ethyl)piperidin-4-yl)-6-methyl-6, 6a, 7, 8, 9, 10-hexahydro-5H-pyrazino[ 1 ', 2 ':4,5]pyrazino-[2, 3-c]pyridazin-2-yl)phenoxy)methyl dihydrogen phosphate

[0307] A solution of 6N HC1 (aq.) (2.0 mL, 12 mmol) was added to the TFA salt of (2-((6S,6aS)-8-(1-(2-((5-((R)-1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1-(4-(4-methyl-thiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)ethyl)piperidin-4-yl)-6-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino-[2,3-c]pyridazin-2-yl)phenoxy)methyl dihydrogen phosphate (26 mg, 21 pmol) and the resulting mixture was stirred at rt for 10 min. The reaction mixture was purified directly by prep-HPLC on a C18 column (5-35% MeCN / 0.05% TFA (aq.)) to afford the TFA salt of the title compound (20 mg, 18 pmol, 76% yield) as a white solid. LCMS calc, for C49H64N10O10PS [M+H]+: m / z = 1015.4; Found: 1016.0.Compound XIII. (25',41?)-l-((l?)-2-(3-(2-(4-(((X)-2-(3-Fluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0308] The title compound was prepared using procedures analogous to those used to synthesize Compound I, utilizing (5)-2-fluoro-6-(8-(piperidin-4-ylmethyl)-6,6a,7,8,9,10-hexa-hydro-5J / -pyrazino[r,2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (Intermediate 11) instead of 2-((65',6a5)-6-methyl-8-(piperidin-4-yl)-6,6a,7,8,9,10-hexahydro-5J / -pyrazino[r,2':4,5]pyrazino-[2,3-c]pyridazin-2-yl)phenol (Intermediate 6). LCMS calc, for C48H60FN10O6S [M+H]+m / z= 923.4; Found 923.5.Compound XIV. (31?,55)-l-((l?)-2-(3-(2-(4-((5)-6a-Ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8 / / -pyrazino| 1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethoxy)-isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)-carbamoyl)pyrrolidin-3-yl dihydrogen phosphate

[0309] The title compound was prepared using procedures analogous to those used to synthesize Compound V, Steps 5-6, utilizing (S)-2-(6a-ethyl-8-(piperidin-4-yl)-6,6a,7,8,9,10-hexahydro-5 / 7-pyrazino[T,2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (Intermediate 12) instead of (65,6a5)-2-(2-(methoxymethoxy)phenyl)-6-methyl-8-(piperidin-4-yl)-6,6a,7,8,9, 10-hexahydro-5 / 7-pyrazino[T,2':4,5]pyrazino[2,3-c]pyridazine (Compound V, Step 4). 'H NMR (400 MHz, DMSO-tC) 8 8.98 (s, 1H), 8.41 (d, J= 7.7 Hz, 1H), 7.89 (d, J= 7.9 Hz, 1H), 7.40 (q, J= 8.3 Hz, 5H), 7.27 - 7.14 (m, 1H), 7.07 (s, 1H), 6.94 - 6.78 (m, 2H), 6.24 - 6.07 (m, 1H), 4.94 (q, J= 7.2 Hz, 1H), 4.63 (s, 1H), 4.58 - 4.48 (m, 1H), 4.48 - 4.38 (m, 1H), 4.37 - 4.27 (m, 1H), 3.77 (t, J= 12.9 Hz, 3H), 3.71 - 3.57 (m, 3H), 3.43 - 3.13 (m, 5H), 3.07 - 2.95 (m, 5H), 2.78 -2.64 (m, 2H), 2.45 (s, 3H), 2.42 - 2.28 (m, 3H), 2.26 - 2.13 (m, 1H), 2.07 - 1.71 (m, 7H), 1.40 (d, = 7.0 Hz, 3H), 1.31 - 1.14 (m, 1H), 0.96 (d, J= 6.6 Hz, 3H), 0.87 - 0.73 (m, 6H). LCMS calc, for C49H64N10O9PS [M+H]+m / z= 999.4; Found 999.3.Example A. SMARCA2 HiBiT and SMARCA4 HiBiT degradation assay (cellular) Preparation of SMARCA2 / 4-HiBiT knock-in cells

[0310] SMARCA2 -HiBiT knock-in Hela monoclonal cell (CS302366) and SMARCA4-HiBiT knock-in Hela monoclonal cell (CS3023226) are purchased from Promega. The heterozygous HiBiT-knock-in is confirmed by sanger sequence in both SMARCA2 -HiBiT and SMARCA4-HiBiT monoclonal cells.SMARCA2 HiBiT and SMARCA4 HiBiT degradation assay in HeLa cells

[0311] Dispense 10 pL aliquot of prepared Hela-SMARCA2 -HiBiT or Hela-SMARCA4-HiBiT cells (1:1 ratio of cells: Trypan Blue (#1450013, Bio-Rad)) onto cell counting slide (#145-0011, Bio-Rad) and obtain cell density and cell viability using cell counter (TC20, Bio-Rad). Remove appropriate volume of resuspended cells from culture flask to accommodate 2500cells / well @ 20 pL / well. Transfer Hela-HiBiT cells to 50ml conical (#430290, Corning). Spin down at 1000 rpm for 5 min using tabletop centrifuge (SPINCHRON 15, Beckman). Discard supernatant and resuspend cell pellet in modified EMEM (#30-2003, ATCC) cell culture media containing 10% FBS (F2422-500ML, Sigma), and IX Penicillin / Streptomycin (200g / l) (30-002-CI, Corning) to a cell density of 125,000 cells / ml. Dispense 20 pL of resuspended Hela-HiBit cells per well in 384-well TC treated plate (#12-565-343, Thermo Scientific) using standard cassette (#50950372, Thermo Scientific) on Multidrop Combi (#5840310, Thermo Scientific) inside laminar flow cabinet.

[0312] Compounds were dissolved in DMSO to make 10 mM stock and 3 -fold series dilutions were further conducted. Dispense test compounds onto plates using digital liquid dispenser (D300E, Tecan). Incubate plates in humidified tissue culture incubator @37 °C for 18 hours. Add 20 pl of prepared Nano-Gio® HiBiT Lytic detection buffer (N3050, Promega) to each well of 384-well plate using small tube cassette (#24073295, Thermo Scientific) on Multidrop Combi, incubate @ RT for 30-60 min. Read plates on microplate reader (Envision 2105, PerkinElmer) using 384 well Ultra-Sensitive luminescence mode. Raw data files and compound information reports are swept into centralized data lake and deconvoluted using automated scripts designed by TetraScience, Inc. Data analysis, curve-fitting and reporting done in Dotmatics Informatics Suite using Screening Ultra module. Results are summarized below in Table 1.Table 1. SMARCA2 and SMARCA4 Degradation

[0313] In Table 1, columns DCso, an “A” denotes DCso < 1 nM; a “B” denotes 1 nM < DCso < 10 nM; a “C” denotes 10 nM < DCso < 100 nM; a “D” denotes DCso > 100 nM.. In Table 1, columns Dmax, an “A” denotes Dmax> 90%; a “B” denotes 50% < Dmax< 90%; a “C” denotes that a Dmax < 50%.Example B. Human liver microsome assay

[0314] Human liver microsomal (HLM) incubations were prepared by combining 0.1 M phosphate buffer (pH 7.4), 600 mM MgCh, microsomes, and the test article. The resulting mixtures were incubated for 5 minutes at 37 °C. Following incubation, one set of samples was activated by NADPH regenerating system, while the second set received an equivalent volume of 0.1 M phosphate buffer. The final concentration of the activated microsomal incubation mixtures was 3 mM MgCh, 1 mM nicotinamide adenine dinucleotide phosphate (NADP), 5 mM glucose-6-phosphate (G6P), and 1 unit / mL glucose-6-phosphate dehydrogenase (G6PDH), 0.5 mg / mL microsomal protein, and 0.5 pM test article or midazolam. Following activation at 37 °C, samples were collected at 0, 5, 10, 15, 30, and 60 minutes. The peak area ratios (PAR) of the analyte and internal standard were determined by LC-MS / MS and were used to calculate clearance. Results are summarized below in Table 2.Table 2. Human Intrinsic ClearanceExample C. Solubility Assay

[0315] Solubility of compounds was measured by comparing UV peak area using a Waters Premier Acquity UPLCMS with a PDA eλ Detector. The mobile phase consisted of (A) water with 0.025% TFA and (B) acetonitrile. The method used an Acquity UPLC CSH C18 column(130A, 1.7 pm, 2.1x50 mm), 3 min runtime, 1 mL / min flowrate at 45 °C, and a 2-100% gradient of B. Solubility samples were sonicated in the aqueous buffer, mixed on a platform rotator for 20 h at rt (23 °C), centrifuged, and supernatant plated and diluted to a 1:1 DMSO:aqueous solution. The solubility was calculated by comparison to a compound calibration curve. For data workup, a relative λmax with a 1 nm window was selected and used for each compound. Buffer was prepared as follows: A 100 mM solution of monopotassium phosphate was titrated with a 100 mM solution of dipotassium phosphate at rt until pH 7.4 was achieved and then diluted to 50 mM with water. Results are summarized below in Table 3.Table 3. Solubility in Buffer (pH 7.4)

[0316] In Table 3, “++++” denotes solubility > 100 pg / mL; “+++” denotes solubility between 10 and 100 pg / mL; “++” denotes solubility between 1 and 10 pg / mL; and “+” denotes solubility between <1 pg / mL.

Claims

What is claimed:

1. A compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:(2S,4R)-4-hydroxy-l-((R)-2-(3-(2-(4-((6S,6aS)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;(2S,4R)-4-hydroxy-l-((R)-2-(3-(2-(4-((6R,6aS)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;(2S,4R)-4-hydroxy-l-((R)-2-(3-(2-(4-((6R,6aR)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;(2S,4R)-4-hydroxy-l-((R)-2-(3-(2-(4-((6S,6aR)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;(3R,5S)-l-((R)-2-(3-(2-(4-((6S,6aS)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl dihydrogen phosphate; or(2-((6£,6a5)-8-(l-(2-((5-((A)-l-((2£,4A)-4-Hydroxy-2-(((5)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-yl)isoxazol-3-yl)oxy)ethyl)piperidin-4-yl)-6-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]-pyrazino[2,3-c]pyridazin-2-yl)phenoxy)methyl dihydrogen phosphate;2. A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:(2S,4R)-4-hydroxy-l-((R)-2-(3-(2-(4-((6S,6aS)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[l',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;(2S,4R)-4-hydroxy-l-((R)-2-(3-(2-(4-((6R,6aS)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[T,2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;(2S,4R)-4-hydroxy-l-((R)-2-(3-(2-(4-((6R,6aR)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[T,2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;(2S,4R)-4-hydroxy-l-((R)-2-(3-(2-(4-((6S,6aR)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[T,2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

3. The compound of any one of claims 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:(2S,4R)-4-hydroxy-l-((R)-2-(3-(2-(4-((6S,6aS)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[T,2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

4. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:(2S,4R)-4-hydroxy-l-((R)-2-(3-(2-(4-((6R,6aS)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[T,2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

5. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:(2S,4R)-4-hydroxy-l-((R)-2-(3-(2-(4-((6R,6aR)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[T,2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-l-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

6. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:(2S,4R)-4-hydroxy-l-((R)-2-(3-(2-(4-((6S,6aR)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

7. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:(3R,5S)-1-((R)-2-(3-(2-(4-((6S,6aS)-2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl dihydrogen phosphate.

8. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:(2-((6S,6aS)-8-(1-(2-((5-((R)-1-((2S,4R)-4-Hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)ethyl)piperidin-4-yl)-6-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]-pyrazino[2,3-c]pyridazin-2-yl)phenoxy)methyl dihydrogen phosphate.

9. A compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:(2S,4R)-1-((R)-2-(3-(2-(4-(((S)-2-(3-Fluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;(3R,5S)-1-((R)-2-(3-(2-(4-((S)-6a-Ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl dihydrogen phosphate; or(3R,5S)-1-((R)-2-(3-(2-(4-((R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl dihydrogen phosphate.

10. The compound of claim 9, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:(2S,4R)-1-((R)-2-(3-(2-(4-(((S)-2-(3-Fluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

11. The compound of claim 9, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:(3R,5S)-1-((R)-2-(3-(2-(4-((S)-6a-Ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl dihydrogen phosphate.

12. The compound of claim 9, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:(3R,5S)-1-((R)-2-(3-(2-(4-((R)-6a-Ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl dihydrogen phosphate.

13. The compound of any one of the preceding claims, in the form of a pharmaceutically acceptable salt.

14. A pharmaceutical composition comprising a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

15. A method of treating cancer in a subject in need thereof comprising administering to the subject a compound of any one of claims 1-13 or a pharmaceutical composition of claim 14.

16. The method according claim 15, wherein the cancer is 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, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinomas.

17. The method according to claim 16, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, soft tissue sarcoma, or penile cancer.

18. The method according to any one of claims 15-17, wherein the cancer is acute myeloid leukemia (AML), 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.

19. A method of degrading a SMARCA2 protein comprising contacting the SMARCA2 protein with a compound of any one of claims 1-13 or a pharmaceutical composition of claim 14.

20. A method of degrading a SMARCA4 protein comprising contacting the SMARCA4 protein with a compound of any one of claims 1-13 or a pharmaceutical composition of claim 14.

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