Compounds targeting BRMs and related uses

Abstract

The present invention is directed to a compound of formula I, which is a SMARCA4 proteolytic factor for the treatment of cancer. JPEG2025521091000237.jpg38133

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority to U.S. Provisional Application No. 63 / 340,185, filed May 10, 2022, which is incorporated herein by reference in its entirety.

[0002] This specification provides bifunctional compounds comprising a target protein - binding moiety and an E3 ubiquitin ligase - binding moiety, and related methods of use. The bifunctional compounds are useful, in particular, as modulators of targeted ubiquitination with respect to the actin - dependent regulator of SWI / SNF - related, matrix - associated, chromatin, subfamily A, member 2 (SMARCA2) (i.e., Brahma or BRM), which are degraded and / or otherwise inhibited by the bifunctional compounds according to this disclosure.

Background Art

[0003] The human switch / sucrose non - fermentable (SWI / SNF) complex is an ATP - dependent chromatin remodeler. These large complexes play important roles in essential cellular processes such as transcription, DNA repair, and replication by regulating DNA accessibility.

[0004] Mutations in genes encoding up to 20 standard SWI / SNF subunits are observed in nearly 20% of all human cancers, with the highest mutation frequencies observed in rhabdoid tumors, cancers in women (including ovarian, uterine, cervical, and endometrial), lung adenocarcinoma, gastric adenocarcinoma, melanoma, esophageal, and renal clear cell carcinoma.

[0005] SMARCA2 (BRM) and SMARCA4 (BRG1) are subunits that contain a catalytic ATP - ase domain, which are essential for the function of SWI / SNF in the disruption of histone - DNA contacts, thereby providing access points for transcription factors and cognate DNA elements that facilitate gene activation and repression.

[0006] SMARCA2 and SMARCA4 share a high degree of homology (up to 75%). SMARCA4 is frequently mutated (i.e., deleted or inactivated) in primary tumors, particularly in lung cancer (12%), melanoma, liver cancer, and pancreatic cancer. SMARCA2 is one of the top essential genes in SMARCA4 mutant (deleted) cancer cell lines. This is because SMARCA4-deleted cancer cells are exclusively dependent on SMARCA2 ATPase activity for their chromatin remodeling activities for cell functions such as cell proliferation, survival, and growth. Thus, targeting SMARCA2 can be a promising therapeutic approach in SMARCA4-related or deficient cancers (genetic synthetic lethality).

[0007] Previous studies have shown strong synthetic lethality using gene expression manipulations such as RNAi. Downregulation of SMARCA2 gene expression in SMARCA4 mutant cancer cells results in suppression of cancer cell proliferation. However, SMARCA2 / 4 bromodomain inhibitors (e.g., PFI-3) show little or no effect on cell growth inhibition [Vangamudi et al. Cancer Res 2015]. This phenotypic discrepancy between gene expression downregulation and small molecule-based approaches led the inventors to investigate proteolytic bispecific molecules in SMARCA4-deficient cancers.

[0008] SMARCA2 has also been reported to play a role in multiple myeloma expressing the t(4;14) chromosomal translocation [Chooi et al. Cancer Res abstract 2018]. SMARCA2 interacts with NSD2 and regulates gene expression such as PRL3 and CCND1. Downregulation of SMARCA2 gene expression by shRNA decreases the S phase of the cell cycle and inhibits cell proliferation of t(4;14) MM cells.

[0009] There is a need for therapeutic compounds that inhibit SMARCA2 and / or SMARCA4. SUMMARY OF THE INVENTION

[0010] The present disclosure relates to a compound of formula (I): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein R1 is halo, C 1-6 alkyl, or haloalkyl, each R2 is independently H, D, or F, each R3 is independently H, D, C 1-6 alkyl, haloalkyl, or C 3-6 cycloalkyl, n is 1, 2, or 3, m is 1, 2, 3, 4, 5, or 6, R4 is H, D, C 1-6 alkyl, C 3-6 cycloalkyl, alkoxyalkyl, cyanoalkyl, or haloalkyl, R5 is H, D, or F, L1 is a bond, C(R3)2, or CO, L2 is a bond, C(R3)2, or CO, ring A1 is a 3- to 7-membered cycloalkyl group, 4- to 7-membered heterocycloalkyl group, aryl group, or heteroaryl group, ring A2 is a 3- to 7-membered cycloalkyl group, 4- to 7-membered heterocycloalkyl group, aryl group, or heteroaryl group, X1 is CH2, CO, CH=CH (when X2 = CO), or N=CH (when X2 = CO), X2 is CH2, CO, CH=CH (when X1 = CO), or N=CH (when X1 = CO), a compound or a pharmaceutically acceptable salt thereof, is targeted.

[0011] Stereoisomers of the compound of formula I, as well as its pharmaceutical salts and stereoisomers, are also contemplated, described, and included herein. Methods of using the compound of formula I, and pharmaceutical compositions containing the compound of formula I are described.

Best Mode for Carrying Out the Invention

[0012] 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 belongs. The terms used herein are for the purpose of describing particular embodiments only and are not intended to limit the disclosure.

[0013] When a range of values is provided, each intervening value, to one tenth of the unit of the lower limit, and any other stated or intervening value within the stated range (such as in the case of a group where each number of carbon atoms within the range is provided), is understood to be included in the disclosure, unless clearly indicated otherwise by the context. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are included within the disclosure, subject to any specifically excluded limits within the stated range. When the stated range includes one or both of the upper or lower limits, ranges excluding either or both of these included upper or lower limits are also included in the disclosure.

[0014] The following terms are used to describe the disclosure. When a term is not specifically defined herein, the term is given the meaning recognized in the art by one of ordinary skill in the art applying the term in the context of describing the disclosure.

[0015] As used in this specification and the appended claims, the articles "a" and "an" are used herein to refer to one or more than one (e.g., at least one) of the grammatical objects of the article, unless the context clearly indicates otherwise. By way of example, "an element" means one element or more than one element.

[0016] The terms "co-administration" and "co-administer" or "combination therapy" refer to both co-administration (administering two or more therapeutic agents simultaneously) and staggered administration (administering one or more therapeutic agents at a time different from the administration of an additional therapeutic agent), so long as the therapeutic agents are present in the patient simultaneously, to some extent, preferably in effective amounts. In certain preferred embodiments, one or more of the compounds of the invention described herein are co-administered, particularly in combination with at least one additional bioactive agent, including an anti-cancer agent. In particularly preferred embodiments, co-administration of the compounds results in synergistic activity and / or treatment, including anti-cancer activity.

[0017] As used herein, the term "compound" refers to any specific chemical compound disclosed herein, unless otherwise indicated, and includes stereoisomers, including tautomers, positional isomers, geometric isomers, and, where applicable, optical isomers (enantiomers, mirror images) and other stereoisomers (diastereomers), and pharmaceutically acceptable salts and derivatives, including, where applicable, prodrugs and / or deuterated forms thereof, within the context of its use. Envisioned deuterated small molecules are those in which one or more of the hydrogen atoms contained in the drug molecule are replaced by deuterium.

[0018] Within the scope of its use in the context, the term "compound" generally refers to a single compound, but may also include stereoisomers, positional isomers and / or optical isomers (including racemic mixtures), and other compounds such as specific enantiomers or enantiomerically enriched mixtures of the disclosed compounds. The term also refers to prodrug forms of the compounds modified to facilitate administration and delivery of the compound to the active site. Note that in describing the compounds of the invention, a number of substituents and variables associated therewith are described, among other things. It will be understood by those skilled in the art that the molecules described herein are stable compounds generally as described below.

[0019] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein and target the substrate protein for degradation. For example, E3 ubiquitin ligase proteins, either alone or in combination with E2 ubiquitin-conjugating enzymes, cause the attachment of ubiquitin to lysine on the target protein and then target specific protein substrates for degradation by the proteasome. Thus, E3 ubiquitin ligase alone or in complex with an E2 ubiquitin-conjugating enzyme is involved in the transfer of ubiquitin to the target protein. Generally, ubiquitin ligases are involved in polyubiquitination, in which a second ubiquitin attaches to the first ubiquitin, a third ubiquitin attaches to the second ubiquitin, and so on. Polyubiquitination marks the protein for degradation by the proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, in which only a single ubiquitin is added to the substrate molecule by the ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation but, instead, their cellular location or function can be altered, for example, by binding to other proteins that have domains capable of binding to ubiquitin. What further complicates the issue is that different lysines on ubiquitin can be targeted by the E3 to form chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to create polyubiquitin that is recognized by the proteasome.

[0020] As used herein, "cereblon (CRBN) E3 ubiquitin ligase" refers to the substrate recognition subunit of the cullin RING E3 ubiquitin ligase complex. CRBN is one of the most common E3 ligases mobilized by bifunctional protein hydrolysis target chimeras (PROTACs) to induce ubiquitination of target proteins and subsequent proteasomal degradation (Maniaci C. et al., Bioorg Med Chem. 2019, 27(12):2466-2479).

[0021] As used herein, the term "alkyl", by itself or as part of another substituent, unless stated otherwise, means a straight or branched chain hydrocarbon radical having up to 12 carbon atoms. In some embodiments, the number of carbon atoms is specified (i.e., C 1- C8 means 1 to 8 carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. The alkyl group may be optionally substituted as provided herein. In some embodiments, the alkyl group is C 1- C6 alkyl, and in some embodiments, this is C 1- C4 alkyl.

[0022] When ranges of carbon atoms such as C1-C6 are used herein, all ranges, as well as the individual numbers of carbon atoms, are included. For example, "C1-C3" includes C 1- C3, C 1- C2, C 2- C3, C1, C2, and C3.

[0023] When used in combination with substituents defined herein, the term "optionally substituted" means that one or more hydrogens of the substituent may be replaced by one or more suitable functional groups or other substituents provided herein, but need not be. For example, the substituent may be halo, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo(C 1-6 )alkyl, C 1-6 alkoxy, halo(C 1-6 alkoxy), C 1-6 alkylthio, C 1-6 alkylamino, NH2, NH(C 1-6 alkyl), N(C 1-6 alkyl)2, NH(C 1-6 alkoxy), N(C 1-6(alkoxy)2, -C(O)NHC 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -C(O)NH2, -C(O)C 1-6 alkyl, -C(O)2C 1-6 alkyl, -NHCO(C 1-6 alkyl), -N(C 1-6 alkyl)CO(C 1-6 alkyl), -S(O)C 1-6 alkyl, -S(O)2C 1-6 alkyl, oxo, 6- to 12-membered aryl, benzyl, pyridinyl, pyrazolyl, thiazolyl, isothiazolyl, or one or more of other 5- to 12-membered heteroaryl groups, which may be optionally substituted. In some embodiments, each of the above optional substituents may itself be optionally substituted by one or two groups.

[0024] The term "optionally substituted -CH2-" refers to "-CH2-" or substituted -CH2-. Substituted -CH2- may also be referred to as -CH(substituent)- or -C(substituent)(substituent)-, and each substituent is independently selected from the optional substituents described herein.

[0025] As used herein, the term "cycloalkyl" refers to a 3- to 12-membered cyclic alkyl, including bridged and spiro rings (e.g., adamantane). The cycloalkyl group may be fully saturated or partially unsaturated. The term "cycloalkyl" also includes polycondensed ring systems (e.g., ring systems containing 2, 3, or 4 rings), and a single cycloalkyl ring (as defined above) may be condensed with one or more groups selected from heterocyclic, carbocyclic, aryl, or heteroaryl groups to form a polycondensed ring system. Such polycondensed ring systems may optionally be substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic moiety of the polycondensed ring. The rings of the polycondensed ring system may be connected to each other via fused, spiro, and bridged bonds, if permitted by valence requirements. It should be understood that the individual rings of the polycondensed ring system may be connected to each other in any order. It should also be understood that the point of attachment of the polycondensed ring system (as defined above for cycloalkyl) may be at any position of the cycloalkyl ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclohexyl, cycloheptyl, cyclooctyl, indenyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[4.1.0]heptanyl, spiro[3.3]heptanyl, and spiro[3.4]octanyl. In some embodiments, the cycloalkyl group is a 3- to 7-membered cycloalkyl.

[0026] As used herein, the term "alkenyl" refers to a C2-C 12 alkyl group containing at least one carbon-carbon double bond. In some embodiments, the alkenyl group may optionally be substituted. In some embodiments, the alkenyl group is a C2-C6 alkenyl.

[0027] As used herein, the term "alkynyl" refers to a C2-C 12Refers to an alkyl group. In some embodiments, the alkenyl group may optionally be substituted. In some embodiments, the alkynyl group is C2-C6 alkynyl.

[0028] The terms "alkoxy", "alkylamino", and "alkylthio" are used in their conventional meanings and refer to an alkyl group bonded to the remainder of the molecule via an oxygen atom ("oxy"), an amino group ("amino"), or a thio group. The term "alkylamino" includes monodialkylamino groups, and the alkyl moieties may be the same or different.

[0029] The term "halo" or "halogen" means a fluorine, chlorine, bromine, or iodine atom, either by itself or as part of another substituent.

[0030] The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms are replaced by a heteroatom selected from S, O, P, and N. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkylamines, alkylamides, alkyl sulfides, and the like. This group may be a terminal group or a crosslinking group. As used herein, references to a straight chain in the context of a crosslinking group refer to the direct chain of atoms connecting the two terminal positions of the crosslinking group.

[0031] As used herein, the term "aryl" refers to a monocyclic all-carbon aromatic ring or a polycondensed all-carbon ring system in which at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 6 to 12 carbon atoms. Aryl includes phenyl radicals. Aryl also includes polycondensed ring systems having about 9 to 12 carbon atoms (e.g., ring systems containing 2, 3, or 4 rings) in which at least one ring is aromatic and the other rings may or may not be aromatic. Such polycondensed ring systems may optionally be substituted on any carbon ring moiety of the polycondensed ring system with one or more (e.g., 1, 2, or 3) oxo groups. The rings of the polycondensed ring system may be connected to each other via fused, spiro, and bridged linkages, where permitted by valence requirements. It should be understood that the point of attachment of a polycondensed ring system as defined above can be at any position of the aromatic ring. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphth-yl, and the like.

[0032] As used herein, the term "heteroaryl" refers to a single aromatic ring having at least one atom other than carbon in the ring, and the atom is selected from the group consisting of oxygen, nitrogen, and sulfur. "Heteroaryl" also includes polycondensed ring systems having at least one such aromatic ring, which are further described below. Thus, "heteroaryl" includes a single aromatic ring having from about 1 to 6 carbon atoms and from about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Sulfur and nitrogen atoms may also be in an oxidized form if the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. "Heteroaryl" also includes polycondensed ring systems (e.g., ring systems containing 2, 3, or 4 rings), and the heteroaryl groups defined above are condensed with one or more rings selected from heteroaryl (e.g., forming naphthyridinyl such as 1,8-naphthyridinyl), heterocyclic (e.g., forming 1,2,3,4-tetrahydro-1,8-naphthyridinyl such as 1,2,3,4-tetrahydronaphthyridinyl), carbocyclic (e.g., forming 5,6,7,8-tetrahydroquinolyl), and aryl (e.g., forming indazolyl) to form a polycondensed ring system. Thus, heteroaryl (single aromatic ring or polycondensed ring system) has from about 1 to 20 carbon atoms and from about 1 to 6 heteroatoms within the heteroaryl ring. Heteroaryl (single aromatic ring or polycondensed ring system) can also have from about 5 to 12 members or from about 5 to 10 members within the heteroaryl ring. The polycondensed ring system may optionally be substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic moiety of the fused ring. The rings of the polycondensed ring system can be connected to each other via condensation, spiro, and bridging bonds when permitted by valence requirements. It should be understood that the individual rings of the polycondensed ring system may be connected to each other in any order. It should also be understood that the point of attachment of the polycondensed ring system (as defined above for heteroaryl) can be at any position of the heteroaryl ring.It should also be understood that the point of attachment of the heteroaryl or heteroaryl polycondensed ring system can be any suitable atom of the heteroaryl ring containing a carbon atom and a heteroatom (e.g., nitrogen). Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl, thianaphthylenyl, pyrrolo[2,3-b]pyridinyl, quinazolin-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole, and 3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole. In one embodiment, the term "heteroaryl" refers to a single aromatic ring containing at least one heteroatom. For example, the term includes 5- and 6-membered monocyclic aromatic rings containing one or more heteroatoms. Non-limiting examples of heteroaryls include, but are not limited to, pyridyl, furyl, thiazole, pyrimidine, oxazole, and thiadiazole.

[0033] The term "heterocyclyl" or "heterocyclic" as used herein refers to a single saturated or partially unsaturated ring having at least one atom other than carbon in the ring, and the atoms are selected from the group consisting of oxygen, nitrogen, and sulfur. This term also includes polycondensed ring systems having at least one such saturated or partially unsaturated ring, which are further described below. For this reason, this term includes a single saturated or partially unsaturated ring (e.g., 3-, 4-, 5-, 6-, or 7-membered ring) having about 1 to 6 carbon atoms and about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. The ring may be substituted with one or more (e.g., 1, 2, or 3) oxo groups, and sulfur and nitrogen atoms may be present in their oxidized forms. Exemplary heterocycles include, but are not limited to, azetidinyl, tetrahydrofuranyl, and piperidinyl. The term "heterocyclic" also includes polycondensed ring systems (e.g., ring systems containing 2, 3, or 4 rings), and a single heterocycle (as defined above) may be condensed with one or more groups selected from heterocycles (e.g., forming 1,8-decahydronaphthyridinyl), carbocycles (e.g., forming decahydroquinolyl), and aryl to form a polycondensed ring system. For this reason, a heterocycle (a single saturated or single partially unsaturated ring or a polycondensed ring system) has about 2 to 20 carbon atoms and 1 to 6 heteroatoms within the heterocycle. Such polycondensed ring systems may optionally be substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic moiety of the polycondensed ring. The rings of the polycondensed ring system may be connected to each other via condensation, spiro, and bridging bonds when permitted by valence requirements. It should be understood that the individual rings of the polycondensed ring system may be connected to each other in any order. Thus, a heterocycle (a single saturated or single partially unsaturated ring, or a polycondensed ring system) has about 3 to 20 atoms containing about 1 to 6 heteroatoms within the heterocyclic system. It should also be understood that the point of attachment (as defined above for heterocyclyl) of the polycondensed ring system can be at any position of the heterocyclyl ring. It should also be understood that the point of attachment of a heterocycle or heterocyclic polycondensed ring system can be any suitable atom of the heterocycle including carbon atoms and heteroatoms (e.g., nitrogen).In one embodiment, the term complex ring is C. 2-20 includes a complex ring. In one embodiment, the term complex ring is C 2-7 includes a complex ring. In one embodiment, the term complex ring is C 2-5 includes a complex ring. In one embodiment, the term complex ring is C 2-4It includes a heterocyclic ring. Exemplary heterocyclic rings include aziridinyl, azetidinyl, pyrrolidinyl, piperidyl, homopiperidyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolinyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, spiro[cyclopropane-1,1’-isoindolinyl]-3’-one, isoindolinyl-1-one, 2-oxa-6-azaspiro[3.3]heptanyl, imidazolidin-2-one N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, 1,4-dioxane, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, pyran, 3-pyrroline, thiopyran, pyrone, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]-heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane, and pyrrolidin-2-one, but are not limited thereto. In one embodiment, the term "heterocyclic ring" refers to a monocyclic saturated or partially unsaturated 3- to 8-membered ring having at least 1 heteroatom. For example, this term includes monocyclic saturated or partially unsaturated 4-, 5-, 6-, or 7-membered rings having at least 1 heteroatom. Non-limiting examples of heterocyclic rings include aziridine, azetidine, pyrrolidine, piperidine, piperidine, piperazine, oxirane, morpholine, and thiomorpholine. As used herein, the term "9-membered or 10-membered hetero-bicyclic" refers to a partially unsaturated or aromatic fused bicyclic ring system having at least 1 heteroatom. For example, the term 9-membered or 10-membered hetero-bicyclic includes a bicyclic ring system having a benzocyclic ring fused to a 5-membered or 6-membered saturated, partially unsaturated, or aromatic ring containing one or more heteroatoms.

[0034] As used herein, the term "heteroatom" means including oxygen (O), nitrogen (N), sulfur (S), and silicon (Si). Nitrogen and sulfur, where possible, may be in oxidized forms.

[0035] As used herein, the term "chiral" refers to a molecule having the property that it cannot be superimposed on its mirror image partner, and the term "achiral" refers to a molecule that can be superimposed on its mirror image partner.

[0036] As used herein, the term "stereoisomer" refers to compounds having the same chemical constitution but differing in the arrangement of atoms or groups in space, such as enantiomers, diastereomers, tautomers.

[0037] The terms "patient" or "subject" are used throughout this specification to describe an animal, preferably a human or livestock, to whom treatment, including prophylactic treatment with a composition according to the present disclosure, is provided. For the treatment of a particular infection, condition, or disease state specific to a particular animal such as a human patient, the term patient refers to that particular animal, including companion animals such as dogs or cats, or livestock such as horses, cows, sheep. Generally, in the present disclosure, the term patient refers to a human patient unless otherwise stated or implied by the context of use of the term.

[0038] The term "effective" is used to describe the amount of a compound, composition, or component that, when used within the context of its intended use, produces the intended result. The term effective encompasses all other terms of effective amount or effective concentration as otherwise described or used in this application.

[0039] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or State government or the corresponding agency of a country other than the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopeias for use in animals, such as humans.

[0040] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure that are pharmaceutically acceptable and have the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. Specifically, examples of such salts include: (1) acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.); or 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-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-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, mucic acid, etc.; or (2) salts formed when the acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion, or coordinated with an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. The salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc. When the compound contains a basic functional group, salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. are included.

[0041] "Pharmaceutically acceptable excipient" refers to a non-toxic, biologically acceptable substance, such as an inert substance that is added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of the agent and is compatible therewith, and is otherwise biologically suitable for administration to a subject. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0042] "Solvate" refers to the physical association of a compound of Formula I with one or more solvent molecules.

[0043] "Treating" or "treatment" of any disease or disorder, in one embodiment, refers to ameliorating the disease or disorder (e.g., preventing or reducing the onset of at least one of the disease or its clinical symptoms). In another embodiment, "treating" or "treatment" refers to improving at least one physical parameter that may not be recognizable by a subject. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder physically (e.g., stabilizing recognizable symptoms), physiologically (e.g., stabilizing physical parameters), or both. In yet another embodiment, "treating" or "treatment" refers to delaying the onset of the disease or disorder.

[0044] In one aspect, the present disclosure provides a compound of formula (I):

Chemical formula

[0045] In some embodiments, R of formula I 1 is halo, C 1-6 alkyl, or haloalkyl. In some embodiments, R of formula I 1 is halo. In some embodiments, R of formula I 1 is C 1-6 alkyl. In some embodiments, R of formula I 1 is haloalkyl.

[0046] In other embodiments, R of formula I 1 is F. In other embodiments, R of formula I 1 is Cl. In other embodiments, R of formula I 1 is methyl.

[0047] In some embodiments, each R2 of Formula I is independently H, D, or F. In some embodiments, each R2 of Formula I is H. In some embodiments, each R2 of Formula I is D. In some embodiments, each R2 of Formula I is F.

[0048] In other embodiments, at least one R2 of Formula I is H. In other embodiments, at least one R2 of Formula I is D. In other embodiments, at least one R2 of Formula I is F.

[0049] In some embodiments, n of Formula (I) is 1, 2, or 3. In some embodiments, n of Formula (I) is 1. In other embodiments, n of Formula (I) is 2. In still other embodiments, n of Formula (I) is 3.

[0050] In some embodiments, each R3 of Formula I is independently H, D, C 1-6 alkyl, haloalkyl, or C 3-6 cycloalkyl. In some embodiments, each R3 of Formula I is H. In some embodiments, each R3 of Formula I is D. In some embodiments, each R3 of Formula I is C 1-6 alkyl. In some embodiments, each R3 of Formula I is haloalkyl. In some embodiments, each R3 of Formula I is C 3-6 cycloalkyl.

[0051] In other embodiments, at least one R3 of Formula I is H. In other embodiments, at least one R3 of Formula I is D. In other embodiments, at least one R3 of Formula I is C 1-6 alkyl. In other embodiments, at least one R3 of Formula I is haloalkyl. In other embodiments, at least one R3 of Formula I is C 3-6 cycloalkyl.

[0052] In some embodiments, m of formula (I) is 1, 2, 3, 4, 5, or 6. In some embodiments, m of formula (I) is 1. In some embodiments, m of formula (I) is 2. In other embodiments, m of formula (I) is 3. In other embodiments, m of formula (I) is 4. In still other embodiments, m of formula (I) is 5. In still other embodiments, m of formula (I) is 6.

[0053] In some embodiments, R4 of formula I is H, D, C 1-6 alkyl, C 3-6 cycloalkyl, alkoxyalkyl, cyanoalkyl, or haloalkyl. In some embodiments, R4 of formula I is H. In some embodiments, R4 of formula I is D. In some embodiments, R4 of formula I is C 1-6 alkyl. In other embodiments, R4 of formula I is haloalkyl. In other embodiments, R4 of formula I is C 3-6 cycloalkyl. In still other embodiments, R4 of formula I is alkoxyalkyl. In still other embodiments, R4 of formula I is cyanoalkyl.

[0054] In some embodiments, R5 of formula I is independently H, D, or F. In some embodiments, R5 of formula I is H. In other embodiments, R5 of formula I is D. In other embodiments, R5 of formula I is F.

[0055] In some embodiments, L1 of formula I is a bond, C(R3)2, or CO. In some embodiments, L1 of formula (I) is a bond. In some embodiments, L1 of formula (I) is C(R3)2. In other embodiments, L1 of formula (I) is CO. In other embodiments, L1 of formula (I) is methylene.

[0056] In some embodiments, L2 of formula I is a bond, C(R3)2, or CO. In some embodiments, L2 of formula (I) is a bond. In some embodiments, L2 of formula (I) is C(R3)2. In other embodiments, L2 of formula (I) is CO. In other embodiments, L2 of formula (I) is methylene.

[0057] In some embodiments, ring A1 of formula (I) is a 3- to 7-membered cycloalkyl group, a 4- to 7-membered heterocycloalkyl group, an aryl group, or a heteroaryl group.

[0058] In some embodiments, ring A1 of formula (I) is a 3- to 7-membered cycloalkyl group. In some embodiments, ring A1 is a 4- to 7-membered heterocycloalkyl group. In other embodiments, ring A1 is aryl. In other embodiments, ring A1 is a heteroaryl group.

[0059] In some embodiments, ring A1 of formula (I) is a cyclohexyl group. In some embodiments, ring A1 of formula (I) is a piperazine group, a morpholine group, a piperidine group, a pyrrolidine group, an azetidine group, or an azabicyclo-hexane group.

[0060] In some embodiments, ring A1 of formula (I) is a piperazine group. In some embodiments, ring A1 of formula (I) is a morpholine group. In other embodiments, ring A1 of formula (I) is a piperidine group. In other embodiments, ring A1 of formula (I) is a pyrrolidine group. In still other embodiments, ring A1 of formula (I) is an azetidine group. In still other embodiments, ring A1 of formula (I) is an azabicyclo-hexane group.

[0061] In some embodiments, ring A2 of formula (I) is a 3- to 7-membered cycloalkyl group, a 4- to 7-membered heterocycloalkyl group, an aryl group, or a heteroaryl group.

[0062] In some embodiments, ring A2 of formula (I) is a 3- to 7-membered cycloalkyl group. In some embodiments, ring A2 is a 4- to 7-membered heterocycloalkyl group. In other embodiments, ring A2 is aryl. In other embodiments, ring A2 is a heteroaryl group.

[0063] In some embodiments, ring A2 of formula (I) is a cyclohexyl group. In some embodiments, ring A2 of formula (I) is a piperazine group, a morpholine group, a piperidine group, a pyrrolidine group, an azetidine group, or an azabicyclo-hexane group.

[0064] In some embodiments, ring A2 of formula (I) is a piperazine group. In some embodiments, ring A2 of formula (I) is a morpholine group. In other embodiments, ring A2 of formula (I) is a piperidine group. In other embodiments, ring A2 of formula (I) is a pyrrolidine group. In still other embodiments, ring A2 of formula (I) is an azetidine group. In still other embodiments, ring A2 of formula (I) is an azabicyclo-hexane group.

[0065] In some embodiments, X1 of formula (I) is CH2, CO, CH=CH (when X2 = CO), or N=CH (when X2 = CO).

[0066] In some embodiments, X1 of formula (I) is CH2. In some embodiments, X1 is CO. In other embodiments, X1 is CH=CH (when X2 = CO). In other embodiments, X1 is N=CH (when X2 = CO).

[0067] In some embodiments, X2 of formula (I) is CH2, CO, CH=CH (when X2 = CO), or N=CH (when X2 = CO).

[0068] In some embodiments, X2 of formula (I) is CH2. In some embodiments, X2 is CO. In other embodiments, X2 is CH=CH (when X1 = CO). In other embodiments, X2 is N=CH (when X1 = CO).

[0069] In some embodiments, the compound of formula (I) is a pharmaceutically acceptable salt. In some embodiments, the compound of formula (I) is a solvate. In some embodiments, the compound of formula (I) is an N-oxide. In some embodiments, the compound of formula (I) is a stereoisomer.

[0070] In some embodiments, the compound of formula (I) is a compound of formula II

Chemical formula

[0071] In some embodiments, each R6 of formula II is independently H, D, C 1-6 alkyl, haloalkyl, or C 3-6 cycloalkyl. In some embodiments, each R6 of formula II is H. In some embodiments, each R6 of formula II is D. In some embodiments, each R6 of formula II is C 1-6 alkyl. In some embodiments, each R6 of formula II is haloalkyl. In some embodiments, each R6 of formula II is C 3-6 cycloalkyl.

[0072] In other embodiments, at least one R6 of formula II is H. In other embodiments, at least one R6 of formula II is D. In other embodiments, at least one R6 of formula II is C 1-6 alkyl. In other embodiments, at least one R6 of formula II is haloalkyl. In other embodiments, at least one R6 of formula II is C 3-6 cycloalkyl.

[0073] In some embodiments, p of formula II is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, p of formula II is 1. In some embodiments, p of formula II is 2. In other embodiments, p of formula II is 3. In other embodiments, p of formula II is 4. In other embodiments, p of formula II is 5. In other embodiments, p of formula II is 6. In still other embodiments, p of formula II is 7. In still other embodiments, p of formula II is 8.

[0074] In some embodiments, Z of formula II is N or CR6. In some embodiments, Z of formula II is N. In some embodiments, Z of formula II is CR6. In some embodiments, Z of formula II is CH3.

[0075] In some embodiments, the compound of formula (I) is a compound of formula III

Chemical formula

[0076] In some embodiments, the compound of formula (I) is a compound of formula IV

Chemical formula

[0077] In some embodiments, the compound of formula (I) is a compound of formula V [Chemical formula] or represented by a pharmaceutically acceptable salt thereof, wherein each R1, R2, (R3) m , R4, and (R6) p are defined with respect to formulas (I) and (II).

[0078] In some embodiments, the compound of formula (I) is a compound of formula VI [Chemical formula] or represented by a pharmaceutically acceptable salt thereof, wherein each R2, R4, and (R6) p are defined with respect to formulas (I) and (II).

[0079] In yet further embodiments, the compound of formula (I) is 3-(6-(4-(((3R,5S)-4-((S)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(3-(((3R,5S)-4-((S)-2-(3-Fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(5-((S)-2-(((3R,5S)-4-((S)-2-(3-Fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)morpholino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-((6aS,9S)-2-(3-Fluoro-2-hydroxyphenyl)-9-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-((S)-2-(3-Fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-(2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 2-(2,6-Dioxopiperidin-3-yl)-5-(4-((4-(2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione, 3-(6-(4-((4-(6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-(2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-(2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-(2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5R)-4-(2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5R)-4-(2-(3-Chloro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-((S)-2-(3,5-Difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((3S,5R)-4-((S)-2-(3,5-Difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3S,5R)-4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-((4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(3-(((3R,5S)-4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(5-((S)-2-(((3R,5S)-4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)morpholino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(3-((4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(3-(((3S,5R)-4-((6aS,9S)-2-(3,5-difluoro-2-hydroxyphenyl)-9-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-((6aS,9S)-2-(3,5-difluoro-2-hydroxyphenyl)-9-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3S,5R)-4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5R)-4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(3-((4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3-ethylpiperazin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-(2-(3-chloro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-(2-(3-chloro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 2-(2,6-Dioxopiperidin-3-yl)-5-(4-((4-(6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione, 3-(6-(4-(((3R,5R)-4-(2-(3,5-Difluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3S,5R)-4-(2-(3,5-Difluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-((S)-2-(3,5-Difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3-ethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 5-(4-(((3S,5R)-4-(2-(3,5-Difluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, 3-(6-((3R,4R)-4-(((1R,5S,6R)-6-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)-3-fluoropiperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-((3R,4R)-4-(((1R,5S,6R)-6-(((6aS,9S)-2-(3,5-difluoro-2-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)-3-fluoropiperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((1R,5S,6r)-6-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)-3,3-difluoropiperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((1R,5S,6r)-6-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)-3,3-difluoropiperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-((rac-3R,4R)-4-(((3S,5R)-4-((S)-2-(3,5-difluorohydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)-3-fluoropiperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-((3R,4R)-3-fluoro-4-(((3S,5R)-4-((S)-2-(3-fluorohydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5R)-4-((S)-2-(3,5-difluorohydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(5-((S)-2-(((3R,5R)-4-((S)-2-(3,5-difluorohydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)morpholino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3S,5S)-4-((S)-2-(3,5-difluorohydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((1-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(2-(((1R,5S,6s)-6-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)morpholino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(2-(((1R,5S,6r)-6-(((6aS,9S)-2-(3,5-difluoro-2-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)morpholino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(5-((S)-2-(((3R,4R)-4-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-3-fluoropiperidin-1-yl)methyl)morpholino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-((S)-3-(((R)-3-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(5-((S)-3-((4-(((S)-2-(3,5-difluoro-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)methyl)pyrrolidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((1S,4r)-4-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-4-fluoropiperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((1R,4s)-4-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((2S,5R)-4-(2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-2,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((1S,4r)-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)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5R)-4-(2-(3-chloro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or a pharmaceutically acceptable salt thereof.

[0080] In yet a further embodiment, the compound of formula (I) is (S)-3-(6-(4-((4-((R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3S,5S)-4-((R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3R,5R)-4-((R)-6a-(Difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((2S,5R)-4-((R)-6a-(Difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-((S)-6a-(Difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-((R)-6a-(Difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((2R,4S,6S)-1-((S)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,6-dimethylpiperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((2R,4R,6S)-1-((R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,6-dimethylpiperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((1-((S)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,2-dimethylpiperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-(((3R,5R)-4-(2-(3-chloro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-(2-(3-chloro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-(((2S,5R)-4-(2-(3-chloro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-(((2S,5R)-4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-(6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-(4-(((3S,5S)-4-(6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-(4-(((3R,5R)-4-(6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-(4-(((3R,5R)-4-(6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-(4-(((2S,5R)-4-(6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-(4-(((3R,5S)-4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-(2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-(2-(3-Fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((2S,5R)-4-(2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((2S,5R)-4-(2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-(2-(3-Chloro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, ((2S,6R)-2,6-Dimethylpiperazin-1-yl)(2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methanone, ((2S,6R)-2,6-Dimethylpiperazin-1-yl)(2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methanone, (3S)-3-(6-(4-(((3S,5R)-4-(2-(3-fluoro-2-hydroxyphenyl)-6a-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-(((3R,5R)-4-(2-(3-fluoro-2-hydroxyphenyl)-6a-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-(((3R,5R)-4-(2-(3-fluoro-2-hydroxyphenyl)-6a-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-(((2R,4r,6S)-1-(2-(3-fluoro-2-hydroxyphenyl)-6a-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-2,6-dimethylpiperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-(((2R,4r,6S)-1-(2-(3-Fluoro-2-hydroxyphenyl)-6a-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,6-dimethylpiperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-(2-(3-Fluoro-2-hydroxyphenyl)-6a-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-(2-(3-Fluoro-2-hydroxyphenyl)-6a-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-(((1s,4R)-4-(2-(3,5-Difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-4-fluorocyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((1R,4R)-4-((S)-2-(3,5-difluorophenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-4-fluorocyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((4-((R)-2-(3,5-difluorophenyl)-6a-(difluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-4-fluoropiperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-(2-(3-chlorophenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-4-fluoropiperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-(6a-ethyl-2-(3-fluorophenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-4-fluoropiperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-(6a-ethyl-2-(3-fluorophenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-4-fluoropiperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-4-fluoropiperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-4-fluoropiperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-fluoro-4-(2-(3-fluorophenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)piperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-4-fluoropiperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-4-fluoropiperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((1S,4r)-4-((S)-2-(3-Fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((1S,4S)-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)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((1R,4r)-4-(((R)-2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((1R,4r)-4-(((R)-2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((1R,4r)-4-(((R)-2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((1R,4r)-4-(((R)-2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-((S)-2-(3,5-Difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((2R,4R,6S)-1-(2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-2,6-dimethylpiperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((2R,4R,6S)-1-(2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-2,6-dimethylpiperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((1-((S)-2-(3-Fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-2,2-dimethylpiperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((1-(2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,2-dimethylpiperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((1-(2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,2-dimethylpiperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or a pharmaceutically acceptable salt thereof.

[0081] In yet a further embodiment, the compound of formula (I) is (S)-3-(6-(4-(((3S,5R)-4-((S)-2-(3-Fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((3S,5R)-4-((R)-2-(3-Fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((3S,5R)-4-((S)-2-(3-Fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3S,5R)-4-((R)-2-(3-Fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(3-(((3R,5S)-4-((S)-2-(3-Fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(3-(((3R,5S)-4-((S)-2-(3-Fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(3-(((3R,5S)-4-((R)-2-(3-Fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(3-(((3R,5S)-4-((R)-2-(3-Fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(5-((S)-2-(((3R,5S)-4-((S)-2-(3-Fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)morpholino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(5-((S)-2-(((3R,5S)-4-((S)-2-(3-Fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)morpholino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(5-((S)-2-(((3R,5S)-4-((R)-2-(3-Fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)morpholino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(5-((S)-2-(((3R,5S)-4-((R)-2-(3-Fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)morpholino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-((4-((S)-2-(3-Fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-((4-((R)-2-(3-Fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((4-((S)-2-(3-Fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((4-((R)-2-(3-Fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-((4-((R)-2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-((4-((S)-2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((4-((R)-2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((4-((S)-2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-((4-((R)-6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-((4-((S)-6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((4-((R)-6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((4-((S)-6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((3R,5S)-4-((S)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((3R,5S)-4-((R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3R,5S)-4-((S)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3R,5S)-4-((R)-2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((3R,5S)-4-((R)-2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((3R,5S)-4-((S)-2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3R,5S)-4-((R)-2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3R,5S)-4-((S)-2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((3R,5R)-4-((S)-2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((3R,5R)-4-((R)-2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3R,5R)-4-((S)-2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3R,5R)-4-((R)-2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((3R,5R)-4-((R)-2-(3-Chloro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((3R,5R)-4-((S)-2-(3-Chloro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3R,5R)-4-((R)-2-(3-Chloro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3R,5R)-4-((S)-2-(3-chloro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((3R,5S)-4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((3R,5S)-4-((R)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3R,5S)-4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3R,5S)-4-((R)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((3R,5S)-4-((R)-2-(3,5-difluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((3R,5S)-4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3R,5S)-4-((R)-2-(3,5-difluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3R,5S)-4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-((4-((R)-2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-((4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((4-((R)-2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((3R,5R)-4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((3R,5R)-4-((R)-2-(3,5-difluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3R,5R)-4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3R,5R)-4-((R)-2-(3,5-difluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((3R,5S)-4-((R)-2-(3-chloro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((3R,5S)-4-((S)-2-(3-chloro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3R,5S)-4-((R)-2-(3-chloro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3R,5S)-4-((S)-2-(3-chloro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((2S,5R)-4-((S)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((2S,5R)-4-((R)-2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((2S,5R)-4-((S)-2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((2S,5R)-4-((R)-2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3R,5S)-4-((S)-2-(3,5-Difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3R,5S)-4-((R)-2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((3R,5S)-4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((3R,5S)-4-((R)-2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3R,5S)-4-((S)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3R,5S)-4-((R)-6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((3R,5S)-4-((S)-6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((3R,5S)-4-((R)-6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((4-((R)-6a-(Difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((4-((S)-6a-(Difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-((4-((S)-6a-(Difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-((4-((R)-6a-(Difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((2R,4S,6S)-1-((S)-6a-(Difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,6-dimethylpiperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((2R,4S,6S)-1-((R)-6a-(Difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,6-dimethylpiperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((2R,4S,6S)-1-((S)-6a-(Difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,6-dimethylpiperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((2R,4S,6S)-1-((R)-6a-(Difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,6-dimethylpiperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((4-((R)-6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((4-((S)-6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-((4-((S)-6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-((4-((R)-6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((2S,5R)-4-((R)-6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((2S,5R)-4-((S)-6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((2S,5R)-4-((R)-6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((2S,5R)-4-((S)-6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((4-((R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((4-((S)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-((4-((R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-((4-((S)-2-(3-Fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((4-((R)-2-(3-Fluoro-2-hydroxyphenyl)-6a-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-((4-((R)-2-(3-Fluoro-2-hydroxyphenyl)-6a-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((4-((S)-2-(3-Fluoro-2-hydroxyphenyl)-6a-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-((4-((S)-2-(3-Fluoro-2-hydroxyphenyl)-6a-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3R,5R)-4-((S)-2-(3-Fluoro-2-hydroxyphenyl)-6a-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((3R,5R)-4-((S)-2-(3-Fluoro-2-hydroxyphenyl)-6a-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3R,5R)-4-((R)-2-(3-Fluoro-2-hydroxyphenyl)-6a-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((3R,5R)-4-((R)-2-(3-Fluoro-2-hydroxyphenyl)-6a-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or a pharmaceutically acceptable salt thereof.

[0082] It will be apparent that the compounds of formula I, including all subgenera described herein, may have multiple stereocenters. As a result, multiple stereoisomers (enantiomers and diastereomers) of the compounds of formula I (and the subgenera described herein) exist. The present disclosure contemplates and encompasses each stereoisomer of any compound of formula I (and the subgenera described herein) and mixtures of such stereoisomers.

[0083] Pharmaceutically acceptable salts and solvates of the compounds of formula I (including all subgenera described herein) are also within the scope of the present disclosure.

[0084] Isotope variants of the compounds of formula I (including all subgenera described herein) are also contemplated by the present disclosure.

[0085] Pharmaceutical Compositions and Methods of Administration The pharmaceutical compositions are typically formulated to provide, as an active ingredient, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof. If desired, the pharmaceutical compositions include carriers comprising pharmaceutically acceptable salts and / or their coordination complexes, as well as one or more pharmaceutically acceptable excipients, inert solid diluents and fillers, diluents comprising sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizing agents, and adjuvants.

[0086] This pharmaceutical composition can be administered alone or in combination with one or more other agents, and these are also typically administered in the form of a pharmaceutical composition. If desired, one or more compounds of the present invention and other agents may be mixed in a formulation, and both components may be formulated into separate formulations and used separately or in combination simultaneously.

[0087] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical composition 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 defined by any two of the above numbers and within the range including them) w / w, w / v, or v / v.

[0088] In some embodiments, the concentration of one or more compounds of the present 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%, or 0.0001% (or a number defined by any two of the above numbers and within the range including them) w / w, w / v, or v / v.

[0089] In some embodiments, the concentration of one or more compounds of the present invention is in the range of about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10% w / w, w / v, or v / v.

[0090] In some embodiments, the concentration of one or more compounds of the present invention is in the range of about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w / w, w / v, or v / v.

[0091] In some embodiments, the amount of one or more compounds of the present invention is 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 defined by and within the range of any two of the above numbers) or less.

[0092] In some embodiments, the amount of one or more compounds of the present 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, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g (or a number defined by and including any two of the above numbers).

[0093] In some embodiments, the amount of one or more compounds of the present 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.

[0094] The compounds according to the present invention are effective over a wide dosage range. For example, in the treatment of adults, dosages of 0.01 - 1000 mg, 0.5 - 100 mg, 1 - 50 mg, and 5 - 40 mg per day are examples of dosages that can be used. An exemplary dosage is 10 - 30 mg per day. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject being treated, the weight of the subject being treated, as well as the preference and experience of the attending physician.

[0095] The pharmaceutical composition of the present invention typically includes the active ingredient of the present invention (e.g., the compound of the present disclosure) 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 solutions and various organic solvents, permeation enhancers, solubilizing agents, and adjuvants.

[0096] Non-limiting exemplary pharmaceutical compositions and methods for preparing the same are described below.

[0097] Pharmaceutical compositions for oral administration In some embodiments, the present invention provides a pharmaceutical composition for oral administration comprising a compound of the present invention and a pharmaceutically acceptable excipient suitable for oral administration.

[0098] In some embodiments, the present invention provides a solid pharmaceutical composition for oral administration comprising (i) an effective amount of a compound of the present invention, optionally (ii) an effective amount of a second agent, and (iii) a pharmaceutically acceptable excipient suitable for oral administration. In some embodiments, the composition further comprises (iv) an effective amount of a third agent.

[0099] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral ingestion. The pharmaceutical composition of the present invention suitable for oral administration can be provided as individual dosage forms such as capsules, cachets, or tablets, or liquids or aerosol sprays, each containing a predetermined amount of the active ingredient as a powder or granule, solution, or suspension in an aqueous or non-aqueous liquid, a water-in-oil emulsion, or an oil-in-water liquid emulsion. Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of associating the active ingredient with a carrier that constitutes one or more necessary components. Generally, the composition is prepared by uniformly and thoroughly mixing the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired form. For example, tablets can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by mixing the active ingredient in a free-flowing form such as a powder or granule, optionally with excipients such as binders, lubricants, inert diluents, and / or surfactants or dispersants, but not limited thereto, and compressing with a suitable machine. Molded tablets can be produced by shaping a mixture of a powdered compound moistened with an inert liquid diluent with a suitable machine.

[0100] Since water can promote the decomposition of some compounds, the present invention further encompasses anhydrous pharmaceutical compositions and dosage forms containing active ingredients. For example, in order to determine characteristics such as shelf life or the stability of the formulation over time, water can be added in the pharmaceutical field (e.g., 5%) as a means of simulating long-term storage. The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-moisture-containing ingredients and low-moisture or low-humidity conditions. The pharmaceutical compositions and dosage forms of the present invention containing lactose can be made anhydrous if they are expected to come into substantial contact with moisture and / or humidity during manufacturing, packaging, and / or storage. The anhydrous pharmaceutical compositions can be prepared and stored such that their anhydrous nature is maintained. Thus, the anhydrous compositions can be packaged using materials known to prevent exposure to water so that they can be included in suitable prescription kits. Examples of suitable packaging include, but are not limited to, sealed foils, plastics, unit-dose containers, blister packs, and strip packs.

[0101] The active ingredient can be combined in intimate mixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the desired form of the formulation for administration. In the preparation of compositions for oral dosage forms, any of the pharmaceutical media can be used as carriers such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc. for oral liquid formulations (such as suspensions, solutions, and elixirs) or aerosols or as carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants, and in some embodiments, can be used without the use of lactose and can be used for oral solid dosage forms. For example, suitable carriers include powders, capsules, and tablets having solid oral formulations. If desired, the tablets can be coated by standard aqueous or non-aqueous techniques.

[0102] 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 rubbers such as gum arabic, sodium alginate, alginic acid, other alginates, tragacanth powder, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropylmethyl cellulose, microcrystalline cellulose, and mixtures thereof.

[0103] Examples of fillers suitable 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, dextrose, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0104] Disintegrants can be used in the compositions of the present invention to provide tablets that disintegrate when exposed to an aqueous environment. If there is too much disintegrant, tablets that can disintegrate within the bottle can be manufactured. If there is too little, it may be insufficient for disintegration to occur, and thus the rate and extent of release of the active ingredient from the dosage form may change. Accordingly, dosage forms of the compounds disclosed herein can be formed using a sufficient amount of disintegrant that is not too little or too much to detrimentally change the release of the active ingredient. The amount of disintegrant used may vary based on the type of formulation and mode of administration and can be readily recognized by those skilled 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 pharmaceutical compositions. Disintegrants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, potassium polyacrylate, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, or mixtures thereof.

[0105] Lubricants that can be used to form the pharmaceutical compositions and dosage forms of the present 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 oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Further lubricants include, for example, syloid silica gel, coagulated aerosol of synthetic silica, or mixtures thereof. The lubricant can be optionally added in an amount of less than about 1 weight percent of the pharmaceutical composition.

[0106] When an aqueous suspension and / or elixir is desirable for oral administration, the active ingredient therein may be combined with diluents such as water, ethanol, propylene glycol, glycerin, and various combinations thereof, along with various sweetening or flavoring agents, coloring agents or dyes, and, if desired, emulsifying and / or suspending agents.

[0107] Tablets may or may not be coated and may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a longer-lasting effect. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be used. Formulations for oral use may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with a water or oil medium (e.g., arachis oil, liquid paraffin, or olive oil).

[0108] Surfactants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be used, a mixture of lipophilic surfactants may be used, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be used.

[0109] Suitable hydrophilic surfactants may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of about 10 or less. The 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 higher solubility in oil, while surfactants with higher HLB values are more hydrophilic and have higher solubility in aqueous solutions.

[0110] Hydrophilic surfactants are generally considered to be compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale generally does not apply. Similarly, lipophilic (e.g., hydrophobic) surfactants are compounds having an HLB value of about 10 or less. However, the HLB value of a surfactant is only a rough guideline generally used to enable the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0111] Hydrophilic surfactants can be either ionic or nonionic. Suitable ionic surfactants include alkylammonium salts, fusidate salts, fatty acid derivatives of amino acids, oligopeptides, and polypeptides, glyceride derivatives of amino acids, oligopeptides, and polypeptides, lecithin and hydrogenated lecithin, lysophosphatidylcholine and hydrogenated lysophosphatidylcholine, phospholipids and their derivatives, lysophospholipids and their derivatives, carnitine fatty acid ester salts, salts of alkyl sulfates, fatty acid salts, sodium docusate, acyl lactylates, mono- and diacetyl tartrate esters of mono- and diglycerides, succinylated mono- and diglycerides, citrate esters of mono- and diglycerides, and mixtures thereof.

[0112] Among the aforementioned groups, examples of ionic surfactants include lecithin, lysophosphatidylcholine, phospholipids, lysophospholipids and their derivatives, carnitine fatty acid ester salts, salts of alkyl sulfates, fatty acid salts, sodium docusate, acyl lactylates, mono- and diacetyl tartrate esters of mono- and diglycerides, succinylated mono- and diglycerides, citrate esters of mono- and diglycerides, and mixtures thereof.

[0113] The ionic surfactant may be in the ionized form of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactic acid esters of fatty acids, stearoyl-2-lactic acid, stearoyl lactate, succinylated monoglyceride, mono / diacetylated tartaric acid esters of mono / diglycerides, citric acid esters of mono / diglycerides, cholylsarcosine, capronate, caprylate, capricate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, cetyl sulfate, docylate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and salts and mixtures thereof.

[0114] Examples of hydrophilic nonionic surfactants include, but are not limited to, polyoxyalkylene alkyl ethers such as alkyl glucosides, alkyl maltosides, alkyl thioglucosides, lauryl macrogol glycerides, and polyethylene glycol alkyl ethers; polyoxyalkylene alkyl phenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid 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 polyol and at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, their derivatives and analogs; polyoxyethylated vitamins and their derivatives; polyoxyethylene-polyoxypropylene block copolymers, and mixtures thereof; polyethylene glycol sorbitan fatty acid esters; and hydrophilic transesterification products of a polyol and 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.

[0115] Examples of other hydrophilic-nonionic surfactants include, but are not limited to, 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 glyceride, PEG-8 caprate / caprylate glyceride, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phytosterol, PEG-30 soy 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 L-oleate, Tween40, Tween60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG10-100 nonylphenol type, PEG15-100 octylphenol type, and poloxamer.

[0116] Suitable lipophilic surfactants include, by way of example only, fatty alcohols, glycerol fatty acid esters, acetylated glycerol fatty acid esters, lower alcohol fatty acid 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 diglycerides, 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, fat-soluble vitamins / vitamin derivatives, and mixtures thereof. Among this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures 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.

[0117] In one embodiment, the composition may contain a solubilizer to ensure good solubilization and / or dissolution of the compounds of the present invention and to minimize precipitation of the compounds of the present invention. This can be particularly important for compositions for parenteral use, such as injectable compositions. Solubilizers can also be added to increase the solubility of hydrophilic drugs and / or other components (such as surfactants) or to maintain the composition as a stable or homogeneous solution or dispersion.

[0118] Examples of suitable solubilizers include alcohols and polyols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, transitol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrin and cyclodextrin derivatives, ethers of polyethylene glycol having an average molecular weight of about 200 to about 6000 such as tetrahydrofurfuryl alcohol PEG ether (glycoflour) or methoxy PEG, amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; citrates such as ethyl propionate, tributyl citrate, acetyltriethyl citrate, acetyltributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizers known in the art such as dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, mono- octanoin, diethylene glycol monoethyl ether, and water, but are not limited thereto.

[0119] A mixture of solubilizers may be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyalkylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, glycol formal, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycol formal, and propylene glycol.

[0120] The amount of solubilizer that may be included is not particularly limited. The amount of a given solubilizer may be limited to a biologically acceptable amount that can be readily determined by one of ordinary skill in the art. In some situations, for example, it may be advantageous to include an amount of solubilizer far in excess of the biocompatible amount in order to maximize the concentration of the drug, and the excess solubilizer is removed using conventional techniques such as distillation or evaporation before the composition is provided to a subject. Thus, when present, the solubilizer may be in a weight ratio of 10 wt%, 25 wt%, 50 wt%, 100 wt%, or up to about 200 wt% based on the combined weight of the drug and other excipients. If desired, very small amounts of solubilizer, such as 5%, 2%, 1% or even less, may also be used. Typically, the solubilizer may be present in an amount of about 1 wt% to about 100 wt%, more typically about 5 wt% to about 25 wt%.

[0121] The composition may further comprise one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, anti-adhesives, anti-foaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicity agents, flavoring agents, coloring agents, odorants, opacifying agents, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0122] In addition, an acid or a base may be incorporated into the present composition for ease of 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, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS), and the like. Bases that are salts of pharmaceutically acceptable acids (e.g., 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, hydroxynaphthalenesulfonic 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, etc.) are also suitable. Salts of polybasic 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 pharmaceutically acceptable cation such as ammonium, an alkali metal, or an alkaline earth metal. Examples include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0123] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic 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 acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroxynaphthalenesulfonic 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.

[0124] Injectable pharmaceutical composition In some embodiments, the present invention provides an injectable pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient suitable for injection. The components and amounts of the agents in the composition are as described herein.

[0125] Forms in which the novel compositions of the present invention can be incorporated for administration by injection include sesame oil, corn oil, cottonseed oil, or peanut oil, and aqueous or oily suspensions, or emulsions, including elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0126] Aqueous solutions in physiological saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. The action of microorganisms can be ensured against by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like.

[0127] The sterile injectable solutions are prepared by incorporating the required amount of the compound of the invention, optionally together with the various other ingredients enumerated above, into a suitable solvent and then filtering sterilizing. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle containing a 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, particular desired methods of preparation are vacuum drying techniques and freeze drying techniques which yield a powder of the active ingredient to which any further desired ingredients have been added from its solution which has been previously sterile filtered.

[0128] Pharmaceutical compositions for topical (e.g., transdermal) delivery In some embodiments, the invention provides a pharmaceutical composition for transdermal delivery comprising a compound of the invention and a pharmaceutically acceptable excipient suitable for transdermal delivery.

[0129] The compositions of the invention can be formulated into preparations in solid, semi-solid, or liquid forms suitable for topical or local administration, such as gels, water-soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, physiological saline, dimethyl sulfoxide (DMSO)-based solutions, etc. Generally, carriers having a higher density can provide a region with long-term exposure to the active ingredient. In contrast, solution formulations can provide more rapid exposure of the active ingredient to the selected region.

[0130] The pharmaceutical composition may also include a suitable solid or gel-phase carrier or excipient, which are compounds that enable or assist the penetration of therapeutic molecules across the stratum corneum permeability barrier of the skin. Many of these penetration enhancing molecules are known to those skilled in the art of topical formulations.

[0131] Examples of such carriers and excipients include, but are not limited to, wetting agents (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), pyrrolidone, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starch, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0132] Another exemplary formulation for use in the methods of the present invention utilizes a transdermal delivery device (a “patch”). Such transdermal patches can be used to provide a controlled amount of continuous or discontinuous infusion of the compounds of the present invention, with or without another agent.

[0133] The construction and use of transdermal patches for the delivery of pharmaceuticals are well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445, and 5,001,139. Such patches can be constructed for continuous delivery, pulsatile delivery, or on-demand delivery of a pharmaceutical.

[0134] Pharmaceutical compositions for inhalation Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Preferably, compositions in pharmaceutically acceptable solvents can be nebulized by the use of an inert gas. Nebulized solutions may be inhaled directly from the nebulizing device, which may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solutions, suspensions, or powder compositions may be administered preferably orally or nasally from a device that delivers the formulation in an appropriate manner.

[0135] other pharmaceutical compositions The pharmaceutical compositions may also be prepared from the compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. The preparation of such pharmaceutical compositions is well known in the art. See, for example, 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 these are hereby incorporated by reference in their entirety.

[0136] Administration of the compounds or pharmaceutical compositions of the present invention can be carried out by any method that enables delivery of the compound to the site of action. These methods include oral route, intraduodenal route, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g., transdermal application), rectal administration, administration via local delivery by catheter or stent, or administration via inhalation. The compound can also be administered into the fat or intrathecally.

[0137] In some embodiments, the compounds or pharmaceutical compositions of the present invention are administered by intravenous injection.

[0138] The amount of the compound to be administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the nature of the compound, and the discretion of the prescribing physician. However, an effective dosage amount is in the range of about 0.001 to about 100 mg / kg body weight / day, preferably about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this is about 0.05 to 7 g / day, preferably about 0.05 to about 2.5 g / day. In some cases, dosage levels below the lower limit of the aforementioned range may be sufficient, while in other cases, even higher dosages may be used without causing harmful side effects, for example, by dividing such higher dosages into several smaller dosages for administration throughout the day.

[0139] In some embodiments, the compounds of the present invention are administered in a single dose.

[0140] Typically, such administration is by injection, for example, intravenous injection, to introduce the drug rapidly. However, other routes may be used as appropriate. A single dose of the compounds of the present invention can also be used for the treatment of acute conditions.

[0141] In some embodiments, the compounds of the present invention are administered in multiple doses. The dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. The dosing may be once per month, once every two weeks, once per week, or once every other day. In another embodiment, the compounds of the present invention and another agent are administered together about once to about six times per day. In another embodiment, the administration of the compounds and agents of the present invention continues for less than about 7 days. In yet another embodiment, the administration continues for more than about 6 days, 10 days, 14 days, 28 days, 2 months, 6 months, or 1 year. In some cases, continuous administration is achieved and maintained as needed.

[0142] The administration of the compounds of the present invention may continue as needed. In some embodiments, the compounds of the present invention are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the compounds of the present invention are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the compounds of the present invention are administered continuously, chronically, for example, for the treatment of chronic effects.

[0143] An effective amount of the compounds of the present invention can be administered by intravenous injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant, either as a single dose or in multiple doses, by any of the acceptable modes of administration of agents having similar utility, including rectal, oral, intranasal, and transdermal routes.

[0144] The compositions of the present invention may also be delivered via an impregnated or coated device such as a stent, or a cylindrical polymer inserted into an artery. Such methods of administration can assist, for example, in preventing or ameliorating restenosis after a procedure such as balloon angioplasty. Without being bound by theory, the compounds of the present invention can delay or inhibit the migration and proliferation of smooth muscle cells in the arterial wall that contribute to restenosis. The compounds of the present invention can be administered, for example, by local delivery from the struts of a stent, from a stent graft, from a graft, or from the cover or sheath of a stent. In some embodiments, the compounds of the present invention are mixed with a matrix. Such a matrix may be a polymer matrix and can serve to bind the compound to the stent. Suitable polymer matrices for such uses include, for example, lactone-based polyesters or copolyesters (e.g., polylactide, polycaprolactone glycolide, polyorthoesters, polyanhydrides, polyamino acids, polysaccharides, polyphosphazenes, poly(ether-ester) copolymers (e.g., PEO-PLLA), polysiloxanes, poly(ethylene-vinyl acetate), acrylate-based polymers or copolymers (e.g., polyhydroxyethyl methyl methacrylate, polyvinylpyrrolidone), fluorinated polymers such as polytetrafluoroethylene, and cellulose esters. Suitable matrices can be non-degradable or can degrade over time and release the compound. The compounds of the present invention can be applied to the surface of a stent by various methods such as dip / spin coating, spray coating, dip coating, and / or brush coating. The compound may be applied in a solvent and the solvent evaporated to form a layer of the compound on the stent. Alternatively, the compound may be placed within the body of the stent or graft, for example, within microchannels or micropores. Upon implantation, the compound diffuses from the stent body and contacts the arterial wall. Such stents may be prepared by immersing a stent manufactured to include such micropores or microchannels in a solution of the compound of the present invention in a suitable solvent and subsequently evaporating the solvent.Excess drug on the surface of the stent may be removed via further short-term solvent washing. In still other embodiments, the compounds of the invention may be covalently attached to the stent or graft. A covalent linker that degrades in vivo to effect release of the compounds of the invention may be used. Any labile in vivo bond such as an ester, amide, or anhydride bond may be used for such purposes. The compounds of the invention may, in addition, be administered intravascularly from a balloon used during angioplasty. Extravascular administration of the compounds by pericardial or adventitial application of the formulations of the invention may also be done to reduce restenosis.

[0145] A variety of stent devices that can be used as described are disclosed, for example, in the following references, all of which are incorporated herein by reference: U.S. Patent No. 5,451,233; U.S. Patent No. 5,040,548; U.S. Patent No. 5,061,273; U.S. Patent No. 5,496,346; U.S. Patent No. 5,292,331; U.S. Patent No. 5,674,278; U.S. Patent No. 3,657,744; U.S. Patent No. 4,739,762; U.S. Patent No. 5,195,984; U.S. Patent No. 5,292,331; U.S. Patent No. 5,674,278; U.S. Patent No. 5,879,382; U.S. Patent No. 6,344,053.

[0146] The compounds of the invention may be administered in a formulation. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of the dosing regimen is necessary for optimal treatment. The dosing of the compounds of the invention can be found by routine experimentation in light of this disclosure.

[0147] If the compounds of the invention are administered in a composition containing one or more agents and the agent has a shorter half-life than the compounds of the invention, the unit dosage forms of the agent and the compounds of the invention may be adjusted accordingly.

[0148] The pharmaceutical composition may be in a form suitable for oral administration, for example, as tablets, capsules, pills, powders, sustained-release preparations, solutions, suspensions, for parenteral injection as sterile solutions, suspensions or emulsions, for topical administration as ointments or creams, or for rectal administration as suppositories. The pharmaceutical composition may be in a unit dosage form suitable for single administration of an exact dosage. The pharmaceutical composition contains a conventional pharmaceutical carrier or excipient and the compound according to the present invention as an active ingredient. Further, it may contain other pharmaceuticals or drugs, carriers, adjuvants, etc. Exemplary parenteral dosage forms include sterile aqueous solutions, for example, solutions or suspensions of the active compound in aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered if desired.

[0149] Method of Use The method typically involves administering a therapeutically effective amount of a compound of the present invention to a subject. The therapeutically effective amount of a combination of compounds of the present invention may vary depending on the intended application (in vitro or in vivo), or the subject and disease state being treated (e.g., the subject's weight and age, the severity of the disease state, the mode of administration, etc.), which can be readily determined by one of ordinary skill in the art. This term also applies to the dosage that induces a specific response in target cells, for example, a decrease in proliferation or a downregulation of the activity of a target protein. The specific dosage will vary depending on the particular compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system by which it is carried.

[0150] In certain embodiments, the present invention provides a pharmaceutical composition comprising a bispecific compound or a pharmaceutically acceptable salt thereof.

[0151] In certain embodiments, the present invention provides a pharmaceutical composition comprising a bispecific compound for use in degrading a target protein in a cell.

[0152] In certain embodiments, a method of degrading a target protein, comprising administering to a cell a therapeutically effective amount of a bispecific compound or a pharmaceutically acceptable salt thereof, wherein the compound is effective to degrade the target protein.

[0153] In certain embodiments, the present invention provides a pharmaceutical composition comprising a bispecific compound for use in the treatment or prevention of a disease or disorder in which SMARCA2 and / or SMARCA4 play a role.

[0154] In certain embodiments, the present invention provides a pharmaceutical composition comprising a bispecific compound for use in the treatment or prevention of a disease or disorder in which an SWI / SNF mutation plays a role.

[0155] In certain embodiments, the target protein is SMARCA2, SMARCA4, and / or PB1.

[0156] In certain embodiments, the target protein complex is SWI / SNF in a cell.

[0157] In certain embodiments, diseases or disorders that are dependent on SMARCA2 or SMARCA4 include cancer.

[0158] In certain embodiments, diseases or disorders that are dependent on the SWI / SNF complex include cancer.

[0159] Exemplary cancers that can be treated with the compounds of the present invention either alone or in combination with at least one additional anti-cancer agent include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and renal cell carcinoma, cancers of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate and stomach; leukemia; benign and malignant lymphomas, particularly Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanomas; myeloproliferative disorders; Ewing sarcoma, angiosarcoma, Kaposi sarcoma, liposarcoma, rhabdomyosarcoma, peripheral neuroepithelial tumor, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, meningioma, glioblastoma, neuroblastoma, gangliocytoma, ganglioglioma: medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma and schwannoma; sarcomas including colorectal 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 teratocarcinoma.

[0160] In certain embodiments, cancers that can be treated using the compounds according to the present disclosure include, for example, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, B-precursor ALL, B-precursor lymphoma, large cell type B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML.

[0161] In certain further embodiments, the cancer is a SMARCA2 and / or SMARAC4-dependent cancer.

[0162] In certain embodiments, the present invention provides a pharmaceutical composition comprising a bispecific compound for use when a disease or disorder dependent on SMARCA2 and / or SMARCA4 is cancer.

[0163] The compounds of the present disclosure, as well as pharmaceutical compositions containing them, can be administered alone or in combination with a medical therapy for treating any of the described diseases. Examples of medical therapies include surgery and radiation therapy (e.g., gamma-ray irradiation, neutron beam radiation therapy, electron beam radiation therapy, proton beam therapy, brachytherapy, systemic radioisotopes).

[0164] In other embodiments, the compounds of the present disclosure, as well as pharmaceutical compositions containing them, can be administered alone or in combination with one or more other agents for treating any of the described diseases.

[0165] In other methods, the compounds of the present disclosure, as well as pharmaceutical compositions containing them, can be administered in combination with an agonist of a nuclear receptor agent.

[0166] In other methods, the compounds of the present disclosure, as well as pharmaceutical compositions containing them, can be administered in combination with an antagonist of a nuclear receptor agent.

[0167] In other methods, the compounds of the present disclosure, as well as pharmaceutical compositions containing them, can be administered in combination with an anti-proliferative agent.

[0168] Combination therapy For treating cancer and other proliferative diseases, the compounds of the present invention can be used in combination with chemotherapeutic agents, agonists or antagonists of nuclear receptors, or other anti-proliferative agents. The compounds of the present invention can also be used in combination with drug therapies such as surgery or radiation therapy (e.g., gamma irradiation, neutron beam radiation therapy, electron beam radiation therapy, proton beam therapy, brachytherapy, and systemic radioisotopes). Examples of suitable chemotherapeutic agents include abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, all-trans retinoic acid, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bendamustine, bevacizumab, bexarotene, bleomycin, bortezomib, bortezomib, busulfan intravenous, busulfan oral, castrone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, drostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan acetate, idarubicin, ifosfamide, imatinib mesylate, interferon alpha 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panobinostat, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin,Any one of pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, lurtotecanib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronic acid is included.

[0169] In some embodiments, the compounds of the present invention can be used in combination with a therapeutic agent that targets an epigenetic regulator. Examples of epigenetic regulators include bromodomain inhibitors, histone lysine methyltransferase inhibitors, histone arginine methyltransferase inhibitors, histone demethylase inhibitors, histone deacetylase inhibitors, histone acetylase inhibitors, and DNA methyltransferase inhibitors. Examples of histone deacetylase inhibitors include, for example, vorinostat. Examples of histone arginine methyltransferase inhibitors include inhibitors of protein arginine methyltransferases (PRMTs) such as PRMT5, PRMT1, and PRMT4. Examples of DNA methyltransferase inhibitors include inhibitors of DNMT1 and DNMT3.

[0170] To treat cancer and other proliferative diseases, the compounds of the present invention can be used in combination with targeted therapies including JAK kinase inhibitors (e.g., ruxolitinib), PI3 kinase inhibitors including P13K-delta selective and broad-spectrum P13K inhibitors, MEK inhibitors, cyclin-dependent kinase inhibitors including CDK4 / 6 inhibitors and CDK9 inhibitors, BRAF inhibitors, mTOR inhibitors, proteasome inhibitors (e.g., bortezomib, carfilzomib), HDAC inhibitors (e.g., panobinostat, vorinostat), DNA methyltransferase 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.

[0171] In some embodiments, the inhibitor of the immune checkpoint molecule is 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, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is atezolizumab, durvalumab, or BMS-935559. In some embodiments, the inhibitor of the 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.

[0172] In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of alkylating agents 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).

[0173] The compounds of the present invention can be prepared using a number of preparative reactions known in the literature. The following schemes provide general guidance related to the preparation of the compounds of the present invention. Those skilled in the art will understand that they can modify or optimize the preparations shown in the schemes using general knowledge of organic chemistry to prepare the various compounds of the present invention. Exemplary synthetic methods for preparing the compounds of the present invention are provided in the following schemes.

[0174] The following examples are provided to illustrate some of the concepts described within the present disclosure. While the examples are considered to provide embodiments, they should not be considered to limit the more general embodiments described herein.

Example

[0175] General Synthetic Procedure The compounds described herein can be prepared according to the following synthetic schemes and general synthetic procedures.

[0176]

Chemical formula

[0177]

Chemical Structure

[0178]

Chemical Structure

[0179]

Chemical Structure

[0180] [Chemical formula] The intermediate of Formula 3-6 where X1 = CO and X2 = CO can be synthesized according to the route described in Scheme 5. S between 5-1 and 3-2 N Compound 3-6 where A2 and R5 are as defined above can be obtained using Ar (e.g., DIPEA).

[0181] [Chemical formula] The compound of Formula (I) can be prepared according to the route described in Scheme 6. Compound 6-2 can be obtained by coupling between 1-8 and 6-1 via any of urea formation (e.g., DIPEA), amide formation (e.g., HATU), or reductive amination (e.g., sodium triacetoxyborohydride). Subsequently, the compound of Formula (I) can be obtained by coupling 6-2 with 3-6 (X1, X2 = CH2 or CO) via either reductive amination (e.g., sodium triacetoxyborohydride) or alkylation (e.g., DIPEA).

[0182] Intermediate 1: (R)-2-Fluoro-6-(6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol [Chemical formula]

[0183] Step 1: (R)-4-(3,6-Dichloropyridazin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl [Chemical formula] A solution of 3,4,6-trichloropyridazine (5.70 g, 31.1 mmol) in DMF (24.0 mL) was added to N,N-diisopropylethylamine (5.95 mL, 34.2 mmol) and (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl (7.10 g, 32.8 mmol). The reaction mixture was stirred at 80 °C overnight. The reaction mixture was cooled to 45 °C and water (17.0 mL) was added slowly. The resulting clear solution was stirred at 35 °C for 30 minutes until a precipitate formed. Another portion of water (23.0 mL) was added slowly and the mixture was stirred at 0 °C for an additional 1 hour. The mixture was filtered and the resulting solid was washed with water, collected, and dried in vacuo to give (R)-4-(3,6-dichloropyridazin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl as an off-white solid (8.50 g, 75% yield). C 14 H 21 Cl2N4O3[M+H] + LCMS calculated value for: m / z = 363.1; found: 363.1.

[0184] Step 2: (R)-3-(azidomethyl)-4-(3,6-dichloropyridazin-4-yl)piperazine-1-carboxylic acid tert-butyl

Chemical Structure

[0185] Step 3: tert-Butyl (S)-2-chloro-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carboxylate

Chem.

[0186] Step 4: (R)-2-chloro-6a,7,9,10-tetrahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylic acid di-tert-butyl

Chem.

Chemical Structure

[0187] Step 5: Di-tert-butyl (R)-2-(3-fluoro-2-hydroxyphenyl)-6a,7,9,10-tetrahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridine-5,8(6H)-dicarboxylate (R)-2-Chloro-6a,7,9,10-tetrahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylic acid di-tert-butyl (1.20 g, 2.82 mmol), (3-fluoro-2-hydroxyphenyl)boronic acid (659 mg, 4.23 mmol), cesium carbonate (2.02 g, 6.20 mmol), and XPhos Pd G2 (333 mg, 0.420 mmol) were degassed. After adding 1,4-dioxane (10 mL) and water (1.30 mL), the reaction was stirred at 80 °C for 6 h. The reaction was filtered and concentrated. The mixture was purified by silica gel flash column chromatography eluting with a gradient of 0 - 45% EtOAc / hexane to give (R)-2-(3-fluoro-2-hydroxyphenyl)-6a,7,9,10-tetrahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylic acid di-tert-butyl (1.10 g, 78% yield). C 25 H 33 Calculated for FN5O5[M+H]+: m / z = 502.3; found: 502.1.

[0188] Step 6: (R)-2-Fluoro-6-(6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol A 4 N solution of HCl in 1,4-dioxane (4.00 mL) was added dropwise to a solution of (R)-2-(3-fluoro-2-hydroxyphenyl)-6a,7,9,10-tetrahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylic acid di-tert-butyl (1.10 g, 2.12 mmol) in DCM (10.0 mL). The reaction was stirred at room temperature for 5 h. The reaction was concentrated under reduced pressure to give (R)-2-fluoro-6-(6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol, dihydrochloride (602 mg, 73% yield) as an off-white solid. C 15 H 17LCMS calculated value for FN5O[M+H]+: m / z = 302.1; measured value: 302.0.

[0189] Intermediate 2: (R)-2,4-difluoro-6-(6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol

Chemical Structure

[0190] Intermediate 3: 2,4-difluoro-6-((6aR,9S)-9-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol

Chemical Structure

[0191] Step 1: O-benzyl-N-(tert-butoxycarbonyl)-L-seryl-L-alanine methyl ester

Chemical Structure

[0192] Step 2: O-benzyl-L-seryl-L-alanine methyl ester

Chemical Structure

[0193] Step 3: (3S,6S)-3-((Benzyloxy)methyl)-6-methylpiperazine-2,5-dione

Chemical Structure

[0194] Step 4: (2R,5S)-2-((Benzyloxy)methyl)-5-methylpiperazine

Chemical Structure

[0195] Step 5: ((2R,5S)-5-Methylpiperazin-2-yl)methanol

Chemical Structure

[0196] Step 6: Di-tert-butyl (2R,5S)-2-(hydroxymethyl)-5-methylpiperazine-1,4-dicarboxylate

Chem.

[0197] Step 7: tert-Butyl (2S,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate

Chem.

[0198] Step 8: (2S,5R)-4-(3,6-Dichloropyridazin-4-yl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl

Chem.

[0199] Step 9: (2S,5R)-5-(Azidomethyl)-4-(3,6-dichloropyridazin-4-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl

Chem.

[0200] Step 10: tert-Butyl (6aS,9S)-2-chloro-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carboxylate

Chem.

[0201] Step 11: Di-tert-butyl (6aR,9S)-2-chloro-9-methyl-6a,7,9,10-tetrahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate

Chem.

[0202] Step 12: (6aR,9S)-2-(3,5-difluoro-2-hydroxyphenyl)-9-methyl-6a,7,9,10-tetrahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylic acid di-tert-butyl

Chem.

[0203] Step 13: 2,4-Difluoro-6-((6aR,9S)-9-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridin-2-yl)phenol

Chemical Structure

[0204] Intermediate 4: ((2S,6R)-2,6-dimethylpiperazin-1-yl)(2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridin-8-yl)methanone (isomer 1)

Chemical formula

[0205] Step 1: (S)-1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid

Chemical formula

[0206] Step 2: 1,4-di-tert-butyl 2-methyl (S)-piperazine-1,2,4-tricarboxylate [Chemical formula] Iodomethane (0.283 mL, 4.55 mmol) was added at 0 °C to a solution of (S)-1,4-bis(tert-butoxycarbonyl)-piperazine-2-carboxylic acid (1.00 g, 3.03 mmol) and potassium carbonate (545 mg, 3.94 mmol) in DMF (10.1 mL). The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl and diluted with water. The aqueous layer was extracted with EtOAc (3 × 25 mL), the combined organic layers were washed with saturated brine solution (1 × 25 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give crude 1,4-di-tert-butyl 2-methyl (S)-piperazine-1,2,4-tricarboxylate (2.14 g). The material was used in the next step without further purification. C7H 13 N2O4 [M + H - C9H 16 O2] + LCMS calculated value for: m / z = 189.1; measured value: 189.0.

[0207] Step 3: 2-Methyl 2-methylpiperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl (racemic mixture)

Chem.

[0208] Step 4: tert-Butyl 2-chloro-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (racemic mixture)

Chem.

[0209] Step 5: Chiral separation of tert-butyl 2-chloro-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (isomers 1 and 2)

Chemical Structure

[0210] Step 6: tert-Butyl 2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazolo[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (isomer 1)

Chem.

[0211] Step 7: tert-Butyl 2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (isomer 1)

Chemical formula

[0212] Step 8: 2-Fluoro-6-(6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridin-2-yl)phenol (isomer 1)

Chem.

[0213] Step 9: tert-Butyl (3R,5S)-4-(chlorocarbonyl)-3,5-dimethylpiperazine-1-carboxylate

Chem.

[0214] Step 10: ((2S,6R)-2,6-Dimethylpiperazin-1-yl)((R)-2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methanone (Isomer 1) Triethylamine (19.4 μL, 139 μmol) and tert-butyl (3R,5S)-4-(chlorocarbonyl)-3,5-dimethylpiperazine-1-carboxylate (12.8 mg, 46.4 μmol) in DCM (1.00 mL) were added to a solution of 2-Fluoro-6-(6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol; dihydrochloride (Isomer 1, 9.00 mg, 20.0 μmol) in DCM (1.15 mL). The reaction was stirred at room temperature overnight. The reaction mixture was quenched with MeOH and saturated aqueous NaHCO3 was added. The aqueous phase was extracted with DCM, the combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was dissolved in DCM (1.15 mL), 2,2,2-Trifluoroacetic acid (53.2 μL, 0.695 mmol) was added, and the reaction was stirred for 1 h. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by preparative HPLC (Waters CSH-C18, 5uM, 30×100 mm, eluting with 6.1 - 26.1% MeCN / water (containing 0.1% TFA) over 5 min) to afford the TFA salt of the title compound as an oil (3.00 mg, 19% yield). C 23 H 31 LCMS calculated for C22H31FN7O2 [M+H]+: m / z = 456.2; found: 456.1.

[0215] Intermediate 5: ((2-(3-chloro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)((2S,6S)-2,6-dimethylpiperazin-1-yl)methanone (isomer 1))

Chem.

[0216] Intermediates 6 - 19: The intermediates shown below in Table 1 were prepared by a method similar to the method described for the preparation of Intermediate 4 using appropriate starting materials.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

[0217] Intermediate 20: 3-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chem.

[0218] Step 1: Methyl 2-cyano-5-(4-(hydroxymethyl)piperidin-1-yl)benzoate

Chem.

[0219] Step 2: Methyl 2-formyl-5-(4-(hydroxymethyl)piperidin-1-yl)benzoate

Chem.

[0220] Step 3: 3-(6-(4-(Hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A stirred solution of methyl 2-formyl-5-(4-(hydroxymethyl)piperidin-1-yl)benzoate (2.40 g, 8.65 mmol) in DCM (48.8 mL) and DMF (48.8 mL) was treated with 3-aminopiperidine-2,6-dione hydrochloride (1.85 g, 11.3 mmol), followed by N,N-diisopropylethylamine (3.77 mL, 21.6 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was cooled to 0 °C and treated with acetic acid (5.94 mL, 104 mmol), followed by sodium triacetoxyborohydride (5.50 g, 26.0 mmol). The reaction mixture was allowed to warm slowly to room temperature and stirred for an additional 3 h. The reaction mixture was diluted with water (10 mL) and the solution was basified with saturated aqueous NaHCO3 until further evolution of gas was not observed. The basified product mixture was filtered and the solid was washed with water (10 mL × 2). The solid was collected and dried in vacuo to afford 3-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione as an off-white solid (1.95 g, 63%). C 19 H 23 N3O4[M+H] + LCMS calculated for: m / z = 358.2; found: 358.1. Intermediates 21 - 26:

[0221] The intermediates shown in Table 2 below were prepared by a method similar to that described for the preparation of Intermediate 20 using the appropriate starting materials.

Table 2

[0222] Intermediate 27: (S)-3-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chem.

[0223] Step 1: tert-Butyl (S)-5-amino-4-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate [Chemical formula] To a solution of methyl 2-formyl-5-[4-(hydroxymethyl)piperidin-1-yl]benzoate (3.0 g, 10.82 mmol) in DCM (45 mL) were added H-Glu(OtBu)-NH2·HCl (2.84 g, 11.9 mmol), acetic acid (1.24 mL, 21.64 mmol), and N,N-diisopropylethylamine (2.07 mL, 11.9 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then cooled to 5 °C. Sodium triacetoxyborohydride (0.840 g, 3.97 mmol) was added portionwise at 5 °C, and then the mixture was stirred at room temperature overnight. After dilution with DCM (45 mL), the reaction was quenched with saturated aqueous NaHCO3 until no further foaming was observed, during which a white precipitate formed. The precipitate was filtered and washed with water and DCM. The solid was collected and dried in vacuo to give a white solid (4.1 g, yield 88%, ee 98.4%). C 23 H 34 N3O 5[M+H] + LCMS calculated value for C: m / z = 432.1; measured value: 432.1

[0224] Step 2: tert-Butyl (S)-4-(6-(4-(acetoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate [Chemical formula] To a stirred solution of tert-butyl (S)-5-amino-4-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (3.00 g, 6.95 mmol) in DCM (30.0 mL) was added N,N-diisopropylethylamine (1.33 mL, 7.65 mmol), followed by acetyl chloride (0.74 mL, 10.4 mmol). The reaction was stirred at room temperature for 2 h. The reaction was quenched with saturated NaHCO3, extracted with DCM, dried over Na2SO4, and purified by flash chromatography using 5% MeOH in DCM to afford a pale yellow solid (3.1 g, 94%). C 25 H 36 N3O6[M+H] + LCMS calculated for: m / z = 474.1; found: 474.1.

[0225] Step 3: (S)-3-(6-(4-(Hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione To a stirred solution of tert-butyl (S)-4-(6-(4-(acetoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate (1.15 g, 2.43 mmol) in MeCN (12.0 mL) was added benzenesulfonic acid (768.0 mg, 4.86 mmol). The reaction mixture was heated to 85 °C. After 2 h, the reaction was cooled to room temperature, water (12 mL) was added, and the reaction was stirred at 75 °C for 4 h until complete conversion was shown by LCMS. The reaction mixture was evaporated to remove volatiles, the residue was cooled to 5 °C, and an aqueous NaHCO3 solution was slowly added until pH = 6 - 7, during which a white precipitate formed. It was filtered and washed with water. The solid was collected and dried in vacuo to afford an off-white solid (730 mg, yield 84%, ee 98.2%). C 19 H 24 N3O4[M+H] + LCMS calculated for: m / z = 358.2; found: 358.1 Intermediate 28

[0226] The intermediates shown below in Table 3 were prepared by the method used for the preparation of Int-27 using appropriate starting materials. [Table 3]

[0227] Intermediate 29: 3-(5-((R)-2-(Hydroxymethyl)morpholino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [Chemical formula]

[0228] Step 1: Methyl (R)-2-cyano-4-(2-(hydroxymethyl)morpholino)benzoate [Chemical formula] To a stirred solution of (R)-morpholin-2-ylmethanol (255 mg, 2.18 mmol) and methyl 2-cyano-4-fluorobenzoate (300 mg, 1.67 mmol) in NMP (6.70 mL) was added N,N-diisopropylethylamine (0.88 mL, 5.02 mmol). The reaction was heated to 120 °C and stirred for 1.5 h. The reaction mixture was cooled to room temperature and diluted with DCM and saturated aqueous brine. The aqueous layer was extracted twice with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography eluting with a gradient of 0-100% EtOAc / hexane to give methyl (R)-2-cyano-4-(2-(hydroxymethyl)morpholino)benzoate as a yellow oil (401 mg, 87% yield). C 14 H 17 N2O4 [M+H] + Calculated LCMS m / z for: m / z = 277.1; found: 277.0.

[0229] Step 2: Methyl (R)-2-formyl-4-(2-(hydroxymethyl)morpholino)benzoate

Chem.

[0230] Step 3: 3-(5-((R)-2-(Hydroxymethyl)morpholino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione N,N-Diisopropylethylamine (0.58 mL, 3.31 mmol) was added to a solution of methyl (R)-2-formyl-4-(2-(hydroxymethyl)morpholino)benzoate (308 mg, 1.10 mmol) and 3-amino-piperidine-2,6-dione, HCl (272 mg, 1.65 mmol) in DCM (5.50 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0 °C, and acetic acid (0.760 mL, 13.2 mmol) and sodium triacetoxyborohydride (701 mg, 3.31 mmol) were added. The reaction mixture was stirred at 0 °C until completion. Saturated aqueous NaHCO3 was added, and the crude reaction mixture was concentrated under reduced pressure. The crude material was dissolved in DMSO, filtered, and the filtrate was purified by preparative HPLC (Waters CSH-C18 column, 7.2 - 27.2% MeCN / water (containing 0.1% TFA) over 5 minutes) to give 3-(5-((R)-2-(hydroxymethyl)morpholino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2,2,2-trifluoroacetic acid (259 mg, 50% yield) as a purple oil. C 18 H 22 N3O5[M+H] + Calculated LCMS m / z for: m / z = 360.2; Found: 360.1.

[0231] Intermediate 30: 2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione

Chem.

[0232] Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione N,N-Diisopropylethylamine (0.380 mL, 2.17 mmol) was added to a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (200 mg, 0.720 mmol) and 4-piperidine-methanol (208 mg, 1.81 mmol) in NMP (7.24 mL). The reaction mixture was heated to 100 °C and monitored by LCMS until completion. The reaction mixture was cooled to room temperature, the solution was filtered, and purified by preparative HPLC (Waters CSH-C18 column, 18.3 - 38.3% MeCN / water (containing 0.1% TFA) over 5 minutes) to afford the TFA salt of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione as a yellow solid (185 mg, 53% yield). C 19 H 22 N3O5[M+H] + Calculated LCMS m / z for: m / z = 372.2; Found: 372.0.

[0233] Intermediate 31: (R)-(6a-(Difluoromethyl)-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)(2,2-dimethylpiperazin-1-yl)methanone

Chemical Structure

[0234] Step 1. 2-Methyl 2-(difluoromethyl)piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl

Chemical Structure

[0235] Step 2. 1,4-Bis(tert-butoxycarbonyl)-2-(difluoromethyl)piperazine-2-carboxylic acid

Chemical formula

[0236] Step 3. 2-chloro-6a-(difluoromethyl)-6-oxo-6a,7,9,10-tetrahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylic acid di-tert-butyl [Chemical Structure] Oxalyl chloride (1.55 mL, 18.1 mmol) was added dropwise to a stirred solution of DMF (1.4 mL, 18.1 mmol) and DCM (35 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 minutes. Next, a solution of 1,4-bis(tert-butoxycarbonyl)-2-(difluoromethyl)piperazine-2-carboxylic acid (5.3 g, 13.9 mmol) and pyridine (1.69 mL, 20.9 mmol) in DCM (10 mL) was added to the reaction mixture at 0 °C. After addition, the reaction mixture was stirred at 0 °C for 30 minutes. Then, the reaction mixture was transferred to a separatory funnel and washed with water (2 × 30 mL) and saturated aqueous sodium chloride solution (30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in DMF (28 mL), and N,N-diisopropylethylamine (7.28 mL, 41.8 mmol) and 4-bromo-6-chloropyridazin-3-amine (2.76 g, 13.2 mmol) were added sequentially. The resulting mixture was stirred at 120 °C overnight. The product mixture was diluted with EtOAc (200 mL) and washed with saturated aqueous sodium chloride solution (2 × 200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography using a gradient of 0 - 100% EtOAc / hexane to obtain tert-butyl 2-chloro-6a-(difluoromethyl)-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carboxylate as a mixture with 4-bromo-6-chloropyridazin-3-amine. The mixture was dissolved in THF (40 mL), and di-tert-butyl dicarbonate (4.8 mL, 20.9 mmol) and 4-(dimethylamino)pyridine (223 mg, 1.82 mmol) were added sequentially. The reaction mixture was stirred for 5 hours. The product mixture was concentrated under reduced pressure.The resulting residue was purified by silica gel flash column chromatography using a gradient of 0 - 100% EtOAc / hexane to give 2-chloro-6a-(difluoromethyl)-6-oxo-6a,7,9,10-tetrahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylic acid di-tert-butyl as a pale yellow foamy solid (523 mg, 8%). C. 20 H 26 ClF2N5O5[M+H] + LCMS calculated value for: m / z = 490.2; found: 489.9

[0237] Step 4. Chiral separation of 2-chloro-6a-(difluoromethyl)-6-oxo-6a,7,9,10-tetrahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylic acid di-tert-butyl

Chemical Structure

[0238] Step 5. (S)-6a-(Difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carboxylic acid tert-butyl

Chemical formula

[0239] Step 6. (R)-6a-(Difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carboxylic acid tert-butyl

Chem.

[0240] Step 7. (S)-2-(6a-(Difluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-2-yl)-6-fluorophenol

Chem.

[0241] Step 8. tert-Butyl 4-(chlorocarbonyl)-3,3-dimethylpiperazine-1-carboxylate

Chem.

[0242] Step 9. (R)-4-(6a-(Difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazine-1-carboxylic acid tert-butyl [Chemical formula] N,N-Diisopropylethylamine (701 μL, 4.0 mmol) and 4-(dimethylamino)pyridine (36.9 mg, 0.30 mmol) were sequentially added to a stirred solution of (S)-2-(6a-(difluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-2-yl)-6-fluorophenol (427 mg, 1.01 mmol) in dimethylacetamide (10 mL) at room temperature. The reaction mixture was stirred for 15 minutes. A solution of tert-butyl 4-(chlorocarbonyl)-3,3-dimethylpiperazine-1-carboxylate (418 mg, 1.51 mmol) in dimethylacetamide (2 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 30 minutes. The product mixture was diluted with EtOAc (100 mL) and washed with saturated aqueous sodium bicarbonate (100 mL). The aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography using a gradient of 0 - 15% MeOH / DCM to give (R)-tert-butyl 4-(6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazine-1-carboxylate (502 mg, 84.3%) as a yellow oil. C 28 H 37 F3N7O4[M+H] + Calculated LCMS value for: m / z = 592.3; Found: 592.2.

[0243] Step 10. (R)-(6a-(Difluoromethyl)-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)(2,2-dimethylpiperazin-1-yl)methanone Trifluoroacetic acid (1.54 mL, 20.1 mmol) was added to a stirred solution of tert-butyl (R)-4-(6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazine-1-carboxylate (502 mg, 0.85 mmol) in DCM (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The product mixture was concentrated under reduced pressure to give the trifluoroacetate salt of (R)-(6a-(difluoromethyl)-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)(2,2-dimethylpiperazin-1-yl)methanone (610 mg, 100%). C 23 H 29 F3N7O2[M+H] + Calculated LCMS value for: m / z = 492.2; Found: 492.0.

[0244] Intermediate 32: ((R)-6a-(Difluoromethyl)-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)((2R,6S)-2,6-dimethylpiperazin-1-yl)methanone

Chemical formula

[0245] Step 1. (S)-6a-(Difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-7,8,9,10-tetrahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-6(6aH)-one

Chemical formula

[0246] Step 2. (3R,5S)-4-((S)-6a-(Difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6-oxo-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl

Chem.

[0247] Step 3. ((R)-6a-(Difluoromethyl)-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)((2R,6S)-2,6-dimethylpiperazin-1-yl)methanone Borane tetrahydrofuran complex (1 M in THF, 0.53 mL, 0.53 mmol) was added to a stirred solution of tert-butyl (3R,5S)-4-((S)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6-oxo-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazine-1-carboxylate (80 mg, 0.132 mmol) in THF (1 mL) at room temperature. The reaction mixture was heated to 60 °C and stirred overnight. The product mixture was cooled to 0 °C and quenched by slowly adding MeOH (2 mL). The quenched product mixture was heated to 80 °C and stirred for 30 minutes. The product mixture was concentrated under reduced pressure. The residue obtained was dissolved in DCM (2 mL). Trifluoroacetic acid (300 μL, 3.96 mmol) was added to the residue in solution and stirred at room temperature for 1 hour. The product mixture was concentrated under reduced pressure. The residue obtained was dissolved in acetonitrile and purified by preparative HPLC (Waters CSH-Flouro-Phenyl, 5 uM, 30×100 mm, eluting with 5 - 25% MeCN / water (containing 0.1% TFA) over 5 minutes) to give ((R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridin-8-yl)((2R,6S)-2,6-dimethylpiperazin-1-yl)methanone (16 mg, 20%) as its TFA salt. C 23 H 28 F3N7O2[M+H] + Calculated LCMS for: m / z = 492.2; Found: 492.1

[0248] Intermediates 33 - 36 The intermediates shown in Table 4 below were prepared by a method similar to that described for the preparation of Intermediate 31 using the appropriate starting materials.

Table 4

[0249] Intermediate 37: (S)-1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-4-carbaldehyde

Chem.

[0250] Step 1. Methyl 2-cyano-5-[4-(hydroxymethyl)piperidin-1-yl]benzoate

Chem.

[0251] Step 2. Methyl 2-cyano-5-(4-formylpiperidin-1-yl)benzoate

Chem.

[0252] Step 3. Methyl 2-cyano-5-[4-(dimethoxymethyl)piperidin-1-yl]benzoate

Chemical formula

[0253] Step 4. Methyl 5-[4-(dimethoxymethyl)piperidin-1-yl]-2-formylbenzoate

Chem.

[0254] Step 5: Methyl (S)-5-amino-4-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate

Chem.

[0255] Step 6: (S)-3-(6-(4-(Dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chemical Structure

[0256] Step 7: (S)-1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-4-carbaldehyde 2,2,2-Trifluoroacetic acid (2.38 mL, 31.1 mmol) was added to a solution of (S)-3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (500 mg, 1.25 mmol) in a 3:1 mixture of DCM (9.3 mL) and acetone (3.1 mL). The reaction was stirred overnight and concentrated under reduced pressure to afford the title compound (440 mg, quantitative yield) as the TFA salt. C 19 H 22 N3O4(M+H) + LCMS calculated m / z = 356.2 for; found: 356.2.

[0257] Intermediate 38: 1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-4-carbaldehyde

Chem.

[0258] Intermediate 39: (S)-3-(1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

Chem.

[0259] Intermediate 40: (2,2-dimethylpiperazin-1-yl)(6a-ethyl-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)methanone (isomer 1)

Chem.

[0260] Step 1. 2-Methyl 2-ethylpiperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl

Chem.

[0261] Step 1,4-bis(tert-butoxycarbonyl)-2-ethylpiperazine-2-carboxylic acid [Chemical formula] Lithium hydroxide (1.25 g, 52.3 mmol) was added to a stirred solution of 1,4-di-tert-butyl 2-methyl 2-ethylpiperazine-1,2,4-tricarboxylate (1.3 g, 3.49 mmol) in THF (30 mL), methanol (10 mL), and water (10 mL). The reaction mixture was stirred overnight. The product mixture was diluted with 1 M aqueous HCl solution (70 mL). The diluted product mixture was extracted with DCM (2 x 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 1,4-bis(tert-butoxycarbonyl)-2-ethylpiperazine-2-carboxylic acid (1.24 g, 99%) as a clear oil. C8H 15N2O4[M + 2H - C9H 16 O2] + LCMS calculated value for: m / z = 203.1; measured value: 203.1.

[0262] Step 3.2 - Synthesis of tert - butyl 2 - chloro - 6a - ethyl - 6 - oxo - 5,6,6a,7,9,10 - hexahydro - 8H - pyrazino[1’,2’:4,5]pyrazino[2,3 - c]pyridazine - 8 - carboxylate

Chemical Structure

[0263] Synthesis of Di-tert-butyl 2-chloro-6a-ethyl-6-oxo-6a,7,9,10-tetrahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate

Chem.

[0264] Chiral Resolution of Di-tert-butyl 2-chloro-6a-ethyl-6-oxo-6a,7,9,10-tetrahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate

Chem.

[0265] Step 6. 6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carboxylic acid tert-butyl (isomer 1)

Chem.

[0266] Step 7. 6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-7,8,9,10-tetrahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridin-6(6aH)-one (isomer 1) [Chemical formula] Hydrochloric acid (4 M in dioxane, 789 μL, 3.16 mmol) was added to a stirred solution of tert-butyl 6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (isomer 1) (140 mg, 0.316 mmol) in DCM (8 mL). The reaction mixture was stirred overnight. The product mixture was concentrated under reduced pressure to afford the HCl salt of 6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-7,8,9,10-tetrahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridin-6(6aH)-one (isomer 1) (120 mg, 100%). C 17 H 19 FN5O2[M+H] + LCMS calculated value for: m / z = 344.2; found: 344.1.

[0267] Step 8. 4-(6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-6-oxo-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl (isomer 1)

Chemical formula

[0268] Step 9. tert-Butyl 4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazine-1-carboxylate (Isomer 1) [Chemical Structure] Borane tetrahydrofuran complex (1 M in THF, 2.33 mL, 2.33 mmol) was added to a stirred solution of tert-butyl 4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6-oxo-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazine-1-carboxylate in THF (9 mL) at room temperature. The reaction mixture was heated to 60 °C and stirred for 5 hours. The reaction mixture was cooled to room temperature and borane tetrahydrofuran complex (1 M in THF, 2.33 mL, 2.33 mmol) was added to the reaction mixture. The reaction mixture was heated to 60 °C and stirred for 3 hours. The product mixture was cooled to 0 °C and quenched by slowly adding MeOH (6 mL). The quenched product mixture was heated to 70 °C and stirred for 3 hours. The product mixture was concentrated under reduced pressure. The residue obtained was purified by silica gel flash column chromatography using a gradient of 0 - 10% MeOH / DCM to give tert-butyl 4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazine-1-carboxylate (isomer 1) (121 mg, 73%). C 29 H 41 FN7O4[M+H] + LCMS calculated value for: m / z = 570.3; found: 570.3

[0269] Step 10. (2,2-Dimethylpiperazin-1-yl)(6a-ethyl-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)methanone (isomer 1) Trifluoroacetic acid (403 μL, 5.3 mmol) was added to a stirred solution of tert-butyl 4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazine-1-carboxylate (120 mg, 0.211 mmol) in DCM (3 mL) at room temperature. The reaction mixture was stirred for 1 hour. The product mixture was concentrated under reduced pressure to afford the TFA salt of (2,2-dimethylpiperazin-1-yl)(6a-ethyl-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)methanone (147 mg, 100%). C 24 H 33 FN7O2[M+H] + LCMS calculated value for: m / z = 470.3; found: 470.1

[0270] Intermediates 41 - 53 The intermediates shown below in Table 5 were prepared by a method similar to the method described for the preparation of Intermediate 40 using appropriate starting materials.

Table 5-1

Table 5-2

Table 5-3

[0271] Intermediate 54: (2,2-Dimethylpiperazin-1-yl)(2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methanone (isomer 2)

Chem.

[0272] Step 1. Synthesis of 2-Methyl 2-(fluoromethyl)piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl

Chem.

[0273] Step 2. Synthesis of 1,4-Bis(tert-butoxycarbonyl)-2-(fluoromethyl)piperazine-2-carboxylic acid

Chem.

[0274] Step 3. 2-Chloro-6a-(fluoromethyl)-6-oxo-6a,7,9,10-tetrahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylic acid di-tert-butyl

Chemical formula

[0275] Step 4. 2-(3-Fluoro-2-methoxyphenyl)-6a-(fluoromethyl)-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carboxylic acid tert-butyl

Chem.

[0276] Step 5. 2-(3-Fluoro-2-methoxyphenyl)-6a-(fluoromethyl)-6a,7,9,10-tetrahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylic acid di-tert-butyl

Chemical Structure

[0277] Step 6. Di-tert-butyl 2-(3-fluoro-2-methoxyphenyl)-6a-(fluoromethyl)-6a,7,9,10-tetrahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate

Chem.

[0278] Step 7. 2-(3-Fluoro-2-methoxyphenyl)-6a-(fluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine (isomer 2)

Chem.

[0279] Step 8. 4-(2-(3-Fluoro-2-methoxyphenyl)-6a-(fluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazine-1-carboxylic acid tert-butyl (isomer 2) [Chemical formula] N,N-Diisopropylethylamine (98 μL, 0.56 mmol) and 4-(dimethylamino)pyridine (5.2 mg, 0.04 mmol) were added to a stirred solution of 2-(3-fluoro-2-methoxyphenyl)-6a-(fluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine (isomer 2) (59 mg, 0.14 mmol) in dimethylacetamide (2 mL) at room temperature. The reaction mixture was stirred for 15 minutes. A solution of tert-butyl 4-(chlorocarbonyl)-3,3-dimethylpiperazine-1-carboxylate (58.7 mg, 0.21 mmol) in dimethylacetamide (1 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 30 minutes. The product mixture was diluted with EtOAc (30 mL) and washed with saturated aqueous sodium bicarbonate (30 mL). The aqueous layer was extracted with EtOAc (2 × 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography using a gradient of 0–15% MeOH / DCM to give tert-butyl 4-(2-(3-fluoro-2-methoxyphenyl)-6a-(fluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazine-1-carboxylate (isomer 2) (78 mg, 91%). C 29 H 40 F2N7O4[M+H] + Calculated LCMS value for: m / z = 588.3; Found: 588.2.

[0280] Intermediate 55: (2,2-Dimethylpiperazin-1-yl)(2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methanone (isomer 2) Boron tribromide (119 μL, 1.25 mmol) was added to a stirred solution of tert-butyl (2,2-dimethylpiperazin-1-yl)(2-(3-fluoro-2-methoxyphenyl)-6a-(fluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazine-1-carboxylate (isomer 2) (74 mg, 0.125 mmol) in DCM (4 mL) at 0 °C. The reaction was warmed to room temperature and stirred for 12 h. The product mixture was cooled to 0 °C and quenched with water (1 mL). The quenched product mixture was transferred to a separatory funnel containing saturated aqueous potassium carbonate (30 mL) and extracted with 3:1 CHCl3:iPrOH (6 × 30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford (2,2-dimethylpiperazin-1-yl)(2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridin-8-yl)methanone (isomer 2) (51 mg, 86%). C 23 H 30 F2N7O2[M+H] + Calculated for LCMS: m / z = 474.2; Found: 474.2.

[0281] Intermediate 56 The intermediates shown in Table 6 below were prepared by a method similar to that described for the preparation of Intermediate 55 using the appropriate starting materials.

Table 6

[0282] Example 1: 3-(6-(4-(((3R,5S)-4-((S)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [Chemical]

[0283] Step 1: ((2R,6S)-2,6-Dimethylpiperazin-1-yl)((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)methanone [Chemical] To a vial containing tert-butyl cis-3,5-dimethylpiperazine-1-carboxylate (206 mg, 0.96 mmol), DCM (4.80 mL) and pyridine (0.190 mL, 2.40 mmol) were added. The reaction mixture was cooled to 0 °C and triphosgene (186 mg, 0.630 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 h. After diluting the reaction mixture with DCM, it was washed with 1 N aqueous HCl. The layers were separated and the aqueous phase was extracted with additional DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was dissolved in DCM (4.80 mL), and 4-fluoro-2-[(10R)-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradeca-2(7),3,5-triene-4-yl]phenol; dihydrochloride (180 mg, 0.480 mmol) and triethylamine (0.340 mL, 2.40 mmol) were added. The reaction mixture was stirred at room temperature overnight. The crude residue was purified by preparative HPLC (Waters CSH-C18, 23.5 - 43.5% MeCN / water (containing 0.1% TFA) over 5 min) to give the Boc intermediate as a brown oil. The residue was dissolved in DCM (4.80 mL), 2,2,2-trifluoroacetic acid (1.10 mL, 14.4 mmol) was added, and the reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure to give ((2S,6R)-2,6-dimethylpiperazin-1-yl)((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)methanone as the TFA salt (119.47 mg, 45% yield). The material was used without further purification. C 22 H 29 FN7O2[M+H] + LCMS calculated for: m / z = 442.2; found: 442.1.

[0284] Step 2: 3-(6-(4-(((3R,5S)-4-((S)-2-(3-Fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A solution of sulfur trioxide pyridine (94.5 mg, 0.590 mmol) in DMSO (0.500 mL) was added dropwise to a vial containing 3-[5-[4-(hydroxymethyl)piperidin-1-yl]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione (70.7 mg, 0.200 mmol, Intermediate 20) and triethylamine (0.250 mL, 1.78 mmol) in DMSO (1.50 mL) while stirring the reaction mixture on ice. After addition was complete, the reaction mixture was warmed to room temperature and stirred for 1 hour. A solution of ((2S,6R)-2,6-dimethylpiperazin-1-yl)((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)methanone; bis-2,2,2-trifluoroacetic acid (55.0 mg, 0.100 mmol) in DMF (1.50 mL) was added to the reaction mixture and stirred for 30 minutes. Acetic acid (0.170 mL, 2.97 mmol) was added, the reaction mixture was cooled to 0 °C, and sodium triacetoxyborohydride (167.86 mg, 0.790 mmol) was added in one portion. The reaction mixture was stirred at 0 °C until completion. Upon completion, water was added and the reaction mixture was stirred for 1 hour. The reaction mixture was filtered and the filtrate was purified by preparative HPLC (Waters CSH-C18, 5uM, 30×100 mm, 9.5 - 19.5% MeCN / water (containing 0.1% TFA) over 5 minutes) to afford 3-(6-(4-(((3R,5S)-4-((S)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione as the TFA salt (36.0 mg, 32% yield). 11H NMR (400 MHz, MeOD) δ 7.46 (d, J = 8.4 Hz, 1H), 7.38 - 7.28 (m, 4H), 7.20 (s, 1H), 7.02 (td, J = 8.1, 4.8 Hz, 1H), 5.14 (dd, J = 13.3, 5.2 Hz, 1H), 4.52 - 4.32 (m, 2H), 4.20 (d, J = 12.8 Hz, 1H), 3.82 (d, J = 12.4 Hz, 2H), 3.79 - 3.70 (m, 2H), 3.62 (d, J = 11.8 Hz, 2H), 3.39 (q, J = 8.1 Hz, 2H), 3.34 - 3.27 (m, 6H), 3.18 - 3.12 (m, 2H), 3.05 (t, J = 12.5 Hz, 1H), 2.98 - 2.84 (m, 5H), 2.79 (dq, J = 17.6, 2.3 Hz, 1H), 2.51 (qd, J = 13.1, 4.6 Hz, 1H), 2.22 - 2.08 (m, 2H), 1.95 (d, J = 12.8 Hz, 2H), 1.52 (q, J = 11.2 Hz, 2H), 1.15 (s, 3H), 1.03 (s, 3H). C 41 H 50 FN 10 O 5[M+H] + Calculated LCMS value for: m / z = 781.4; Observed: 781.3.

[0285] Examples 2 - 36: The examples shown in Table 7 below were prepared as the TFA salts by the method used in the preparation of Example 1 using appropriate intermediates and starting materials.

Table 7 - 1

Table 7 - 2

Table 7 - 3

Table 7 - 4

Table 7 - 5

Table 7 - 6

Table 7-7

Table 7-8

Table 7-9

Table 7-10

Table 7-11

Table 7-12

Table 7-13

[0286] Examples 37 and 38: 3-(6-((3R,4R)-4-(((1R,5S,6R)-6-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-yl)methyl)-3-fluoropiperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (isomers 1 and 2)

Chemical formula

[0287] Step 1. (1R,5S,6s)-6-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl

Chemical formula

[0288] Step 2. 2-((S)-8-(((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-2-yl)-4,6-difluorophenol

Chemical Structure

[0289] Step 3. Methyl ((3R,4R)-1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3-fluoropiperidin-4-yl)4-methylbenzenesulfonate (isomers 1 and 2)

Chem.

[0290] Step 4. 3-[5-[(3R,4R)-4-[[(1S,5R)-6-[[(10S)-4-(3,5-difluoro-2-hydroxyphenyl)-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradeca-2(7),3,5-triene-12-yl]methyl]-3-azabicyclo[3.1.0]hexan-3-yl]methyl]-3-fluoropiperidin-1-yl]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione (isomers 1 and 2) 2-[(10S)-12-[[(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-1,5,6,8,12-pentaazatricyclo-[8.4.0.02,7]tetradeca-2,4,6-triene-4-yl]-4,6-difluorophenol;dihydrochloride (20.0 mg, 41.0 μmol), ((rac-3R,4R)-1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3-fluoro-piperidin-4-yl) methyl 4-methyl-benzenesulfonate (24.0 mg, 45.1 μmol), N,N-diisopropyl-ethylamine (42.9 μL, 0.246 mmol), and sodium iodide (12.3 mg, 82.1 μmol) in DMF (1.00 mL) were stirred at 130 °C for 1 h. The crude mixture reaction mixture was diluted with DMSO (15.0 mL), filtered, and the filtrate was purified by preparative HPLC on a C18 column (7.6 - 27.6% MeCN in 0.1% TFA (aqueous solution), pH = 2) to give the TFA salt of the title compound as a white solid (2.50 mg, yield 7.6%, peak 2, isomer 2, Example 38 5790) and (0.6 mg, 1.9%, peak 1, isomer 1, Example 37 5789). C 40 H 45 F3N9O4[M+H] + Calculated LCMS value for: m / z = 772.4; found: 772.1.

[0291] Examples 39 - 41: The examples shown in Table 8 below were prepared as TFA salts by the method used for the preparation of Examples 37 and 38 using the appropriate intermediates and starting materials.

Table 8

[0292] Examples 42 and 43: 3-(6-((rac-3R,4R)-4-(((3S,5R)-4-((S)-2-(3,5-difluorophenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)-3-fluoropiperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (isomers 1 and 2)

Chemical formula

[0293] Example 44 The examples shown below in Table 9 were prepared as TFA salts by the method used for the preparation of Examples 42 and 43 using appropriate intermediates and starting materials. [Table 9]

[0294] Example 45: 3-(6-(4-(((3R,5R)-4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [Chemical formula]

[0295] Step 1: (R)-2-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)oxy)-3,5-difluorophenyl)-6a,7,9,10-tetrahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylic acid 5-((9H-fluoren-9-yl)methyl) 8-(tert-butyl) [Chemical formula] (10R)-4-Chloro-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradeca-2(7),3,5-triene-8,12-dicarboxylic acid di-tert-butyl (300 mg, 0.700 mmol, Intermediate 1, Step 4), (3,5-difluoro-2-hydroxyphenyl)boronic acid (135 mg, 0.770 mmol), cesium carbonate (504.5 mg, 1.55 mmol), and XPhos Pd G2 (83.1 mg, 0.110 mmol) in a mixture of 1,4-dioxane (4.00 mL) and water (0.500 mL) were degassed with N2, and the reaction mixture was stirred at 120 °C for 2 hours. The mixture was diluted with DCM and washed with saturated brine solution. The aqueous phase was extracted with DCM, the combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was suspended in a mixture of 1,4-dioxane (4.00 mL) and water (0.500 mL), and 9-fluorenylmethoxycarbonyl chloride (401 mg, 1.55 mmol) was added, followed by sodium bicarbonate (355 mg, 4.23 mmol). After stirring at room temperature for 4 hours, an additional portion of 9-fluorenylmethoxycarbonyl chloride (401 mg, 1.55 mmol) and sodium bicarbonate (355 mg, 4.23 mmol) were added. The reaction was stirred at room temperature overnight. The reaction mixture was diluted with DCM and water. The layers were separated, the combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography eluting with a gradient of 0-100% EtOAc / hexane to give (R)-2-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)oxy)-3,5-difluorophenyl)-6a,7,9,10-tetrahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylic acid 5-((9H-fluoren-9-yl)methyl) 8-(tert-butyl) (492 mg, 81% yield). C 50 H 44 F2N5O7[M+H] + Calculated LCMS value for: m / z = 864.3; Found: 864.3.

[0296] Step 2: (R)-2-(2-((((9H-Fluoren-9-yl)methoxy)carbonyl)oxy)-3,5-difluorophenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-5-carboxylic acid (9H-fluoren-9-yl)methyl

Chem.

[0297] Step 3: ((S)-2-(3,5-Difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)((2R,6R)-2,6-dimethylpiperazin-1-yl)methanone

Chem.

[0298] Step 4: 3-(6-(4-(((3R,5R)-4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A procedure similar to the one described for the preparation in Step 2 of Example 1 was used, replacing ((S)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)((2R,6R)-2,6-dimethylpiperazin-1-yl)methanone; 2,2,2-trifluoroacetic acid with ((2S,6R)-2,6-dimethylpiperazin-1-yl)((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)methanone; 2,2,2-trifluoroacetic acid to prepare the title compound. C 41 H 49 F2N 10 O5[M+H] + LCMS calculated value for: m / z = 799.4; measured value: 799.2. Examples 46 - 47:

[0299] The examples shown in Table 10 below were prepared as TFA salts by the method used for the preparation of Example 45, using the appropriate intermediates and starting materials.

Table 10

[0300] Example 48: 3-(6-(4-((1-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chem.

[0301] Step 1. Piperidine-4-carbaldehyde

Chem.

[0302] Step 2. (S)-1-(2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)piperidine-4-carbaldehyde

Chem.

[0303] Step 3: 3-(1-Oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

Chemical Structure

[0304] Step 4: 3-(6-(4-((1-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (S)-1-(2-(3,5-Difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]-pyrazino[2,3-c]pyridazine-8-carbonyl)piperidine-4-carbaldehyde; 2,2,2-trifluoroacetic acid (34.0 mg, 0.060 mmol), 3-(1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione; hydrochloride) (33.0 mg, 90.0 μmol), magnesium sulfate (29.0 mg, 0.240 mmol), and sodium acetate (28.0 mg, 0.340 mmol) in DMSO (1.00 mL) were stirred at 40 °C for 45 minutes. Sodium triacetoxyborohydride (55.0 mg, 0.26 mmol) was added and the reaction was stirred at room temperature for 6 hours. The reaction was quenched with water (1.0 mL) and diluted with DMSO (15.0 mL). The mixture was filtered and the filtrate was purified by preparative HPLC on a C18 column (7.6 - 27.6% MeCN / 0.1% TFA (aqueous solution), pH = 2) to give the TFA salt of the title compound as a white solid (32.0 mg, 30% yield). C 39 H 45 F2N 10 O5[M+H] + Calculated LCMS value for: m / z = 771.4; Observed: 771.2.

[0305] Example 49: 3-(6-(2-(((1R,5S,6s)-6-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)morpholino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chemical Structure

[0306] Examples 50 - 53: The examples shown in Table 11 below were prepared as TFA salts by the method described for the preparation of Example 49 using appropriate intermediates and starting materials.

Table 11

[0307] Example 54: 3-(6-(4-(((1S,4r)-4-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chemical Structure

[0308] Step 1: ((1r,4r)-4-(((Tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclohexyl)methanol

Chem.

[0309] Step 2: (1r,4r)-4-(((Tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclohexane-1-carbaldehyde

Chem.

[0310] Step 3: 3-(1-Oxo-6-(4-(((1r,4r)-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclohexyl)methyl)piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

Chemical Structure

[0311] Step 4: 3-(6-(4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [Chemical formula] To a 20 mL vial containing a solution of 3-(1-oxo-6-(4-(((1r,4r)-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclohexyl)methyl)piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (30.0 mg, 60.0 μmol) in DCM (0.25 mL) and methanol (0.25 mL), p-TSOH H2O (1.50 mg, 0.01 mmol) in a 1:1 mixture of DCM (0.250 mL) and methanol (0.250 mL) was added. The reaction mixture was stirred at 35 °C for 72 h. The crude reaction mixture was diluted with methanol (5 mL), and the product was purified by preparative HPLC (Waters CSH Phenyl-hexyl, 5 uM, 30×100 mm, 5 min gradient from 5.8 to 25.8% MeCN / water (containing 0.1% TFA)) to afford the TFA salt of 3-(6-(4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione as a white solid (13 mg, 51% yield). C 25 H 35 N4O4[M+H] + LCMS calculated value for: m / z = 455.3; found: 455.2

[0312] Step 5: 3-(6-(4-(((1S,4r)-4-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A procedure similar to the one described for the preparation of Example 49 was carried out, replacing 3-[5-[2-(hydroxymethyl)morpholin-4-yl]-3-oxo-1H-isoindol-2-yl]-piperidine-2,6-dione with 3-(6-(4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, and using 2-[(10S)-12-[[(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradeca-2(7),3,5-triene-4-yl]-4,6-difluorophenol; 2,2,2-trifluoroacetic acid in place of Intermediate 2, to prepare the title compound. C 40 H 48 F2N9O4[M+H] + LCMS calculated value for: m / z = 756.4; measured value: 756.3.

[0313] Example 55: 3-(6-(4-((4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-4-fluoropiperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chemical formula

[0314] Step 1: (S)-4-(2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl

Chemical formula

[0315] Step 2: (S)-(2-(3,5-Difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridin-8-yl)(4-fluoropiperidin-4-yl)methanone

Chemical Structure

[0316] Step 3: 3-(6-(4-((4-((S)-2-(3,5-Difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-4-fluoropiperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-[5-[4-(Hydroxymethyl)piperidin-1-yl]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione (22.0 mg, 60.0 μmol, Intermediate 20) was dissolved in DMSO (1.00 mL), and then triethylamine (80.0 μL, 0.550 mmol) was added. Sulfur trioxide pyridine (29.3 mg, 0.180 mmol) in DMSO (500 μL) was added dropwise, and the reaction mixture was stirred for 1 hour. After 1 hour, [(10S)-4-(3,5-difluoro-2-hydroxyphenyl)-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradeca-2(7),3,5-triene-12-yl]-(4-fluoropiperidin-4-yl)methanone; dihydrochloride (16.0 mg, 30.0 μmol) and acetic acid (50 μL, 0.920 mmol) were added in ACN (1.00 mL). The mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (52.0 mg, 0.250 mmol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was purified by preparative HPLC (Waters CSH C18, 5 uM, 30×100 mm, eluting with 7.7 - 27.7% MeCN / water (containing 0.1% TFA) over 5 minutes) to give the TFA salt of 3-(6-(4-((4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-4-fluoropiperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (6.20 mg, yield 26%). C 40 H 45 F3N9O5[M+H] + Calculated LCMS value for: m / z = 788.4; Observed: 788.1.

[0317] Example 56: 3-(6-(4-(((1R,4s)-4-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chem.

[0318] Step 1: (1s,4s)-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclohexane-1-carboxylic acid

Chem.

[0319] Step 2: ((1s,4s)-4-(((Tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclohexyl)methanol [Chemical formula] (1s,4s)-4-(((Tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclohexane-1-carboxylic acid (135 mg, 0.560 mmol) was dissolved in THF (1.11 mL), and then cooled to 0 °C. Borane tetrahydrofuran (0.560 mL, 0.560 mmol) was added dropwise. After stirring the reaction mixture at 0 °C for 10 minutes, it was slowly warmed to room temperature. After 5 hours, the reaction was quenched with MeOH, concentrated under reduced pressure, taken up in EtOAc, and poured into water. The aqueous phase was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with water, followed by brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give ((1s,4s)-4-(((Tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclohexyl)methanol as a clear oil (75.5 mg, 59% yield). Note: The product did not ionize and was used directly in the next step without further purification.

[0320] Step 3: 3-(1-Oxo-6-(4-(((1s,4s)-4-(((Tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclohexyl)methyl)piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione [Chemical formula] ((1s,4s)-4-(((Tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclohexyl)methanol (28.7 mg, 0.13 mmol) was dissolved in DMSO (1.2 mL) and triethylamine (0.14 mL, 1.01 mmol). The reaction mixture was cooled to 0 °C, and a solution of sulfur trioxide pyridine (107 mg, 0.670 mmol) in DMSO (1.20 mL) was added dropwise. After leaving at room temperature for 3.5 h, 3-(3-oxo-5-piperazin-1-yl-1H-isoindol-2-yl)piperidine-2,6-dione (41.3 mg, 0.130 mmol, Example 48, Step 3), MeCN (1.20 mL), and acetic acid (0.25 mL, 4.4 mmol) were added. After stirring the reaction mixture at room temperature for 15 min, sodium triacetoxyborohydride (92.9 mg, 0.44 mmol) was added. After 3 h, the reaction was quenched with water, diluted with 20 mL of DMSO, and loaded onto an LCMS automated purification system (17.6 - 37.6% ACN / water 0.1% TFA over 5 min, Waters CSH-C18 column) to give 3-(1-oxo-6-(4-(((1s,4s)-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclohexyl)methyl)piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (33 mg, 50%) as its TFA salt (white powder). C 30 H 43 N4O5[M+H] + Calculated LCMS value for: m / z = 539.3; Found: 539.2.

[0321] Step 4: 3-(6-(4-(((1s,4s)-4-(Hydroxymethyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chem.

[0322] Step 5: 3-(6-(4-(((1R,4s)-4-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(6-(4-(((1S,4S)-4-(Hydroxymethyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (21.0 mg, 50.0 μmol) was dissolved in DMSO (500 μL), triethylamine; TEA (50.0 μL, 0.390 mmol). The reaction mixture was cooled to 0 °C and sulfur trioxide pyridine (42.0 mg, 0.26 mmol) in DMSO (0.5 mL) was added dropwise. After 3 h at room temperature, (R)-2,4-difluoro-6-(6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (14.7 mg, 50.0 μmol, Intermediate 2), MeCN (1.00 mL), and acetic acid (110 μL, 1.85 mmol) were added and the mixture was stirred for 80 min. Then sodium triacetoxyborohydride (48.96 mg, 0.23 mmol) was added and the reaction mixture was stirred at room temperature. After stirring overnight, the reaction was quenched with water, diluted with 15 mL of DMSO, and directly purified using an LCMS automated purification system (10.4 - 23.4% ACN / water 0.1% TFA over 5 min, Waters CSH-C18 column) to give 3-(6-(4-(((1R,4S)-4-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (9.80 mg, 19%) as the white solid TFA salt. C 40 H 48 F2N9O4[M+H] + LCMS calculated for: m / z = 756.4; found: 756.2.

[0323] Example 57: 3-(6-(4-(((2S,5R)-4-(2-(3-Fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chem.

[0324] Example 58: 3-(6-(4-(((1S,4r)-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)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chem.

[0325] Example 59: 3-(6-(4-(((3R,5S)-4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (isomer 1)

Chem.

[0326] Example 60: 3-(6-(4-(((3R,5S)-4-(6a-ethyl-2-(3-fluorophenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (isomer 1)

Chem.

[0327] Example 61: 3-(6-(4-(((3R,5S)-4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (isomer 2)

Chemical Structure

[0328] Example 62: 3-(6-(4-(((3R,5S)-4-(6a-ethyl-2-(3-fluorophenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (isomer 2)

Chemical Structure

[0329] Example 63: 3-(6-(4-(((3R,5R)-4-(2-(3-chloro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (isomer 2) [Chemical formula] Using appropriate starting materials and intermediates and a procedure similar to that described for Example 1, the title compound was prepared as the TFA salt. C 42 H 52 ClN 10 O5[M+H] + LCMS calculated value for: m / z = 811.4; measured value: 811.0.

[0330] Example 64: 3-(6-(4-(((3R,5S)-4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (isomer 2) [Chemical formula] Using appropriate starting materials and intermediates and a procedure similar to that described for Example 1, the title compound was prepared as the TFA salt. C 42 H 51 F2N 10 O5[M+H] + LCMS calculated value for: m / z = 813.4; measured value: 813.1.

[0331] Example 65: (S)-3-(6-(4-((4-((R)-6a-(Difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [Chemical formula] Sodium triacetoxyborohydride (719 mg, 3.4 mmol) was added to a stirred solution of acetic acid (0.48 mL, 4.24 mmol), (R)-(6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridin-8-yl)(2,2-dimethylpiperazin-1-yl)methanone (610 mg, 0.85 mmol), and Intermediate 38 (445 mg, 1.28 mmol) in DMF (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The product mixture was diluted with DMSO and purified by preparative HPLC (Waters CSH-C18, 5 uM, 30×100 mm, 8.1 - 28.1% MeCN / water (containing 0.1% TFA) over 5 minutes) to give (S)-3-(6-(4-((4-((R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione as its TFA salt (235 mg, 24%). 11H NMR (400 MHz, MeOD) δ 7.46 (s, 1H), 7.39 - 7.28 (m, 5H), 7.03 (s, 1H), 6.27 (t, J = 54.6 Hz, 1H), 5.13 (d, J = 13.4 Hz, 1H), 4.38 (s, 3H), 4.18 (s, 1H), 4.01 (d, J = 9.9 Hz, 1H), 3.90 - 3.76 (m, 3H), 3.65 - 3.35 (m, 7H), 3.15 (s, 4H), 2.97 - 2.84 (m, 4H), 2.78 (d, J = 17.6 Hz, 1H), 2.49 (q, J = 13.8 Hz, 1H), 2.16 (s, 2H), 1.91 (d, J = 12.6 Hz, 2H), 1.66 - 1.37 (m, 9H). C 42 H 50 F3N 10 O5[M + H] + Calculated LCMS value for: m / z = 831.4; Measured value: 831.3.

[0332] Examples 66 - 70 Examples 66 - 70 shown in Table 12 below were prepared as TFA salts by the method used in the preparation of Example 65 using appropriate intermediates and starting materials.

Table 12 - 1

Table 12 - 2

[0333] Example 71. (S)-3-(6-(4-(((2R,4S,6S)-1-((S)-6a-(Difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,6-dimethylpiperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Chemical Structure

[0334] Step 1. (2R,4r,6S)-4-(Hydroxymethyl)-2,6-dimethylpiperidine-1-carboxylic acid tert-butyl

Chem.

[0335] Step 2. Methyl ((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)benzoate

Chem.

[0336] Step 3. Methyl ((2R,4r,6S)-1-(chlorocarbonyl)-2,6-dimethylpiperidin-4-yl)benzoate

Chemical Structure

[0337] Step 4. Methyl ((2R,4S,6S)-1-((S)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-2,6-dimethylpiperidin-4-yl)benzoate [Chemical formula] Methyl ((2R,4r,6S)-1-(chlorocarbonyl)-2,6-dimethylpiperidin-4-yl)benzoate (252 mg, 0.81 mmol) in a solution of dimethylacetamide (1 mL) was added to a stirred solution of (R)-2-(6a-(difluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazin-2-yl)-6-fluorophenol (230.0 mg, 54 mmol), N,N-diisopropylethylamine (378 μL, 2.2 mmol), and 4-(dimethylamino)pyridine (20 mg, 0.16 mmol) in dimethylacetamide (4 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. The product mixture was quenched with water (20 mL). The diluted product mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography using a gradient of 0 - 15% MeOH / DCM to give methyl ((2R,4S,6S)-1-((S)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1’,2’:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-2,6-dimethylpiperidin-4-yl)benzoate (195 mg, 58%). C 32 H 36 F3N6O4 [M + H] + LCMS calculated value for: m / z = 625.3; measured value: 625.2

[0338] Step 5. ((S)-6a-(Difluoromethyl)-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)((2R,4S,6S)-4-(hydroxymethyl)-2,6-dimethylpiperidin-1-yl)methanone

Chem.

Claims

1. Compound of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof R １ But, hello, C １－６ Alkyl or haloalkyl, Each R ２ However, independently, they are H, D, or F. Each R ３ However, independently, H, D, C １－６ Alkyl, haloalkyl, or C ３－６ It is a cycloalkyl, n is 1, 2, or 3, m is 1, 2, 3, 4, 5, or 6. R ４ is H, D, C １－６ alkyl, C ３－６ cycloalkyl, alkoxyalkyl, cyanoalkyl, or haloalkyl, and R ５ However, it is H, D, or F. L １ However, bond, C(R ３ ) ２ , or CO, L ２ However, bond, C(R ３ ) ２ , or CO, Ring A １ However, it is a 3-7 membered cycloalkyl group, a 4-7 membered heterocycloalkyl group, an aryl group, or a heteroaryl group. Ring A ２ However, it is a 3-7 membered cycloalkyl group, a 4-7 membered heterocycloalkyl group, an aryl group, or a heteroaryl group. X １ However, CH ２ , CO, CH=CH(X ２ =CO case), or N=CH(X ２ = (in the case of CO) X ２ However, CH ２ , CO, CH=CH(X １ =CO case), or N=CH(X １ A compound or a pharmaceutically acceptable salt thereof (in the case of CO).

2. R １ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is a halo and optionally F.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 1, n is 2, or n is 3.

4. Each R ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is F, or each R2 is H.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein m is 1, m is 2, m is 3, m is 4, m is 5, or m is 6.

6. (a) Each R ３ H is; and / or (b) R4 is H, R4 is D, R4 is C1-6 alkyl, or R4 is methyl; and / or (c) R 5 is H, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

7. (a) L １ L1 is CO, L1 is C(R3)2, or L1 is a methylene group; and / or (b) L2 is CO, L2 is C(R3)2, or L2 is a methylene group. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

8. (a) Ring A １ is a 3- to 7-membered cycloalkyl group, and optionally ring A1 is a cyclohexyl group; or (b) Ring A1 is a 4- to 7-membered heterocycloalkyl group, and optionally, (i) Ring A １ is a piperazine group, a morpholine group, a piperidine group, a pyrrolidine group, an azetidine group, or an azabicyclohexane group; or (ii) Ring A １ This is a piperazine group. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

9. (a) Ring A ２ is a 3- to 7-membered cycloalkyl group, and optionally ring A2 is a cyclohexyl group; or (b) Ring A2 is a 4- to 7-membered heterocycloalkyl group, and optionally, (i) Ring A2 is a piperazine group, a morpholine group, a piperidine group, a pyrrolidine group, an azetidine group, or an azabicyclohexane group; or (ii) Ring A2 is a piperidine group, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

10. (a)X １ CH ２ Either X1 is CO; and / or (b) X2 is CH2 or X2 is CO The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. Compounds of formula II: 【Chemistry 2】 or a pharmaceutically acceptable salt thereof Each R ６ However, independently, H, D, C １－６ Alkyl, C ３－６ It is a cycloalkyl or haloalkyl, p is 1, 2, 3, 4, 5, 6, 7, or 8, Z is N or CR ６ And; Optional, (a) Z is N, p is 1, p is 2, p is 3, p is 4, p is 5, p is 6, p is 7, or p is 8; and / or (b) Each R ６ Is H, or each R ６ C １－６ Alkyl or each R ６ is methyl, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

12. Compounds of formula III: 【Transformation 3】 or its pharmaceutically acceptable salt; or Compounds of formula IV: 【Chemistry 4】 or its pharmaceutically acceptable salt; or Compound of formula V: 【Transformation 5】 or its pharmaceutically acceptable salt; or Compounds of formula VI: 【Transformation 6】 or a pharmaceutically acceptable salt thereof The compound according to claim 11 or a pharmaceutically acceptable salt thereof.

13. 3-(6-(4-(((3R,5S)-4-((S)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(3-(((3R,5S)-4-((S)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)azetidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(5-((S)-2-(((3R,5S)-4-((S)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)morpholino)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-(((6aS,9S)-2-(3-fluoro-2-hydroxyphenyl)-9-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-((((S)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-(2-((3-fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 2-(2,6-dioxopiperidine-3-yl)-5-(4-((4-(2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)isoindoline-1,3-dione, 3-(6-(4-((4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-(2-((3-fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-(2-((3-fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-((((3R,5R)-4-(2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5R)-4-(2-(3-chloro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-(((3S,5R)-4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3S,5R)-4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (R)-3-(6-(4-((4-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((4-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(3-(((3R,5S)-4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)azetidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(5-((S)-2-(((3R,5S)-4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)morpholino)-1-oxoisoindoline-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(3-((4-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazine-1-yl)methyl)azetidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(3-(((3S,5R)-4-((6aS,9S)-2-(3,5-difluoro-2-hydroxyphenyl)-9-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)azetidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-(((6aS,9S)-2-(3,5-difluoro-2-hydroxyphenyl)-9-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3S,5R)-4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5R)-4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(3-((4-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3-ethylpiperazine-1-yl)methyl)azetidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-(2-(3-chloro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-(2-((3-chloro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 2-(2,6-dioxopiperidine-3-yl)-5-(4-((4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)isoindoline-1,3-dione, 3-(6-(4-(((3R,5R)-4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3S,5R)-4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3-ethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 5-(4-(((3S,5R)-4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione, 3-(6-((3R,4R)-4-(((1R,5S,6R)-6-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-yl)methyl)-3-fluoropiperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-((3R,4R)-4-(((1R,5S,6R)-6-(((6aS,9S)-2-(3,5-difluoro-2-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-yl)methyl)-3-fluoropiperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((1R,5S,6r)-6-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-yl)methyl)-3,3-difluoropiperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((1R,5S,6r)-6-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-yl)methyl)-3,3-difluoropiperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-((rac-3R,4R)-4-(((3S,5R)-4-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)-3-fluoropiperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-((3R,4R)-3-fluoro-4-(((3S,5R)-4-((S)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5R)-4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(5-((S)-2-(((3R,5R)-4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)morpholino)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3S,5S)-4-((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-((1-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)piperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(2-(((1R,5S,6s)-6-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-yl)methyl)morpholino)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(2-(((1R,5S,6r)-6-(((6aS,9S)-2-(3,5-difluoro-2-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-yl)methyl)morpholino)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(5-((S)-2-(((3R,4R)-4-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-3-fluoropiperidine-1-yl)methyl)morpholino)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-((S)-3-(((R)-3-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)pyrrolidine-1-yl)methyl)pyrrolidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(5-((S)-3-((4-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidine-1-yl)methyl)pyrrolidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((1S,4r)-4-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)cyclohexyl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-4-fluoropiperidine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((1R,4s)-4-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-((((2S,5R)-4-(2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,5-dimethyl-piperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((1S,4r)-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)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethyl-piperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethyl-piperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethyl-piperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethyl-piperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-((((3R,5R)-4-(2-(3-chloro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethyl-piperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethyl-piperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, or a pharmaceutically acceptable salt thereof; or (S)-3-(6-(4-((4-(((R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3S,5S)-4-((R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((3R,5R)-4-((R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((2S,5R)-4-((R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-(((S)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-((R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((2R,4S,6S)-1-((S)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,6-dimethylpiperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((2R,4R,6S)-1-((R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,6-dimethylpiperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((1-(((S)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,2-dimethylpiperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-(((3R,5R)-4-(2-(3-chloro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethyl-piperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-(2-(3-chloro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((((2S,5R)-4-(2-(3-chloro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,5-dimethyl-piperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((((2S,5R)-4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3S,5S)-4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5R)-4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5R)-4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((2S,5R)-4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethyl-piperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethyl-piperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-(2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-(2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,3-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-((((2S,5R)-4-(2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-((((2S,5R)-4-(2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-(2-(3-chloro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethyl-piperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, ((2S,6R)-2,6-dimethylpiperazine-1-yl)(2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methanone, ((2S,6R)-2,6-dimethylpiperazine-1-yl)(2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methanone, (3S)-3-(6-(4-((((3S,5R)-4-(2-(3-fluoro-2-hydroxyphenyl)-6a-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-(((3R,5R)-4-(2-(3-fluoro-2-hydroxyphenyl)-6a-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-(((3R,5R)-4-(2-(3-fluoro-2-hydroxyphenyl)-6a-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-(((2R,4r,6S)-1-(2-(3-fluoro-2-hydroxyphenyl)-6a-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,6-dimethylpiperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-(((2R,4r,6S)-1-(2-(3-fluoro-2-hydroxyphenyl)-6a-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,6-dimethylpiperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-(2-(3-fluoro-2-hydroxyphenyl)-6a-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-(2-(3-fluoro-2-hydroxyphenyl)-6a-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperazine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-(((1s,4R)-4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-4-fluorocyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((1R,4R)-4-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-4-fluorocyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((4-(((R)-2-(3,5-difluoro-2-hydroxyphenyl)-6a-(difluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-4-fluoropiperidine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-(2-(3-chloro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-4-fluoropiperidine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-4-fluoropiperidine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-(6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-4-fluoropiperidine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-4-fluoropiperidine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-4-fluoropiperidine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-fluoro-4-(2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)piperidine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-4-fluoropiperidine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((4-(2-(3,5-difluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-4-fluoropiperidine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((1S,4r)-4-((S)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)cyclohexyl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((1S,4S)-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)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((1R,4r)-4-(((R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)cyclohexyl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((1R,4r)-4-(((R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)cyclohexyl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((1R,4r)-4-(((R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(((1R,4r)-4-(((R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-(((S)-2-(3,5-difluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,3-dimethylpiperidine-1-yl)methyl)piperidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((((2R,4R,6S)-1-(2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,6-dimethylpiperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((((2R,4R,6S)-1-(2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,6-dimethylpiperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, 3-(6-(4-((1-((S)-2-(3-fluoro-2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-2,2-dimethylpiperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((1-(2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,2-dimethylpiperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, (3S)-3-(6-(4-((1-(2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carbonyl)-2,2-dimethylpiperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione, or a pharmaceutically acceptable salt thereof The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

15. A pharmaceutical composition according to claim 14 for treating cancer, wherein optionally, (a) The cancer is a SMARCA4 deletion cancer; or (b) The cancers described above include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and renal cell carcinoma, cancers of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovaries, pancreas, prostate and stomach; leukemia; benign and malignant lymphomas, especially Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myasthenia, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, nerve Sarcomas including glioblastoma, neuroblastoma, gangliocytoma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma and Schwann cell tumor; colorectal 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 teratoma, wherein the lung cancer is optionally SMARCA4-deficient non-small cell lung cancer; or (c) The cancer is T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, B-progenitor cell ALL, B-progenitor cell lymphoma, large B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, and Philadelphia chromosome-positive CML. Pharmaceutical composition.