6, 6A, 7, 8, 9, 10-hexahydro-5H-pyrazino [1apos; 6, 6A, 7, 8, 9, 10-hexahydro-5H-pyrazino [1apos; , 2apos; 4, 5) pyrazino [2, 3-c] pyridazine derivatives

Abstract

The present invention relates to compounds of formula I. The compounds of the present invention are SMARCA4 protein degradation agents for the treatment of cancer. # imgabs0 #

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 340,185, filed May 10, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure provides bifunctional compounds comprising a target protein binding portion and an E3 ubiquitin ligase binding portion and related methods of use. The bifunctional compounds are useful as modulators of targeted ubiquitination, particularly for Switch / Sucrose Non-Fermentable (SWI / SNF)-Related, Matrix-Associated, Actin-Dependent Regulator of Chromatin, Subfamily A, Member 2 (SMARCA2) (i.e., BRAHMA or BRM), which is degraded and / or otherwise inhibited by the bifunctional compounds according to the present disclosure. Background Art

[0004] Human switch / sucrose non-fermentable type (SWI / SNF) complexes are ATP-dependent chromatin remodelers. These large complexes play important roles in essential cellular processes such as transcription, DNA repair, and replication by regulating DNA accessibility.

[0005] Mutations in genes encoding up to 20 canonical SWI / SNF subunits are observed in approximately 20% of all human cancers, with the highest frequencies observed in rhabdoid tumors, female cancers (including ovarian, uterine, cervical, and endometrial cancers), lung adenocarcinoma, gastric adenocarcinoma, melanoma, esophageal cancer, and renal clear cell carcinoma.

[0006] SMARCA2 (BRM) and SMARCA4 (BRG1) are subunits containing a catalytic ATPase domain and are essential for SWI / SNF function in disrupting histone-DNA contacts, thereby providing entry points for transcription factors and cognate DNA elements, promoting gene activation and repression.

[0007] 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 most important genes in SMARCA4 mutant (deleted) cancer cell lines. This is because SMARCA4-deficient cancer cells are completely dependent on SMARCA2 ATPase activity to achieve their chromatin remodeling activity, thereby achieving cellular functions such as cell proliferation, survival, and growth. Therefore, targeting SMARCA2 may be a promising treatment method for SMARCA4-associated or defective cancers (genetic synthetic lethality).

[0008] Previous studies have demonstrated strong synthetic lethality using gene expression manipulation (such as RNAi); downregulating SMARCA2 gene expression in SMARCA4 mutant cancer cells results in inhibition of cancer cell proliferation. However, SMARCA2 / 4 bromodomain inhibitors (e.g., PFI-3) exhibit no or minimal effects on cell proliferation inhibition [Vangamudi et al. Cancer Res 2015]. This phenotypic difference between gene expression downregulation and small molecule-based approaches led us to investigate bispecific molecules for protein degradation in SMARCA4-deficient cancers.

[0009] SMARCA2 has also been reported to play a role in multiple myeloma expressing the t(4;14) chromosomal translocation [Chooi et al., Cancer Research, 2018]. SMARCA2 interacts with NSD2 and regulates the expression of genes such as PRL3 and CCND1. Downregulation of SMARCA2 gene expression using shRNA shortens the S phase of the cell cycle and inhibits cell proliferation in t(4;14) MM cells.

[0010] There is a need for therapeutic compounds that inhibit SMARCA2 and / or SMARCA4. Summary of the Invention

[0011] The present disclosure relates to compounds of formula (I):

[0012]

[0013] or a pharmaceutically acceptable salt thereof; wherein

[0014] R1 is halogen, C 1-6 Alkyl or haloalkyl;

[0015] Each R2 is independently H, D or F;

[0016] Each R3 is independently H, D, C 1-6 Alkyl, haloalkyl or C 3-6Cycloalkyl;

[0017] n is 1, 2, or 3;

[0018] m is 1, 2, 3, 4, 5 or 6;

[0019] R4 is H, D, C 1-6 Alkyl, C 3-6 a cycloalkyl group, an alkoxyalkyl group, a cyanoalkyl group, or a haloalkyl group;

[0020] R5 is H, D or F;

[0021] L1 is a bond, C(R3)2 or CO;

[0022] L2 is a bond, C(R3)2 or CO;

[0023] Ring A1 is a 3-7 membered cycloalkyl group, a 4-7 membered heterocycloalkyl group, an aryl group or a heteroaryl group;

[0024] Ring A2 is a 3-7 membered cycloalkyl group, a 4-7 membered heterocycloalkyl group, an aryl group or a heteroaryl group;

[0025] X1 is CH2CO, CH=CH (when X2=CO) or N=CH (when X2=CO); and

[0026] X2 is CH2CO, CH=CH (when X1=CO) or N=CH (when X1=CO).

[0027] Stereoisomers of the compounds of Formula I, as well as pharmaceutically acceptable salts and stereoisomers, are also contemplated, described, and encompassed herein. Methods of using the compounds of Formula I and pharmaceutical compositions comprising the compounds of Formula I are described. DETAILED DESCRIPTION

[0028] 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 in this specification are for the purpose of describing specific embodiments only and are not intended to limit the disclosure.

[0029] Where a range of values ​​is provided, it is understood that each intervening value (to one-tenth of the unit of the lower limit) between the upper and lower limits of the range (such as in the case of a group containing a number of carbon atoms, in which case each number of carbon atoms falling within the range is provided) and any other specified or intervening value within the specified range is encompassed within the disclosure unless the context clearly dictates otherwise. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the disclosure, subject to any explicitly excluded limit in the specified range. Where the specified range includes one or both of the limits, ranges excluding one or both of those included limits are also encompassed within the disclosure.

[0030] The following terms are used to describe the present disclosure. Where a term is not specifically defined herein, the term is given the art-recognized meaning by those of ordinary skill in the art as the term is applied to the context in which it is used to describe the present disclosure.

[0031] Unless the context clearly dictates otherwise, as used herein and in the claims, the articles "a" and "an" are used herein to refer to one or to more than one (e.g., to at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.

[0032] The term "co-administration" or "combination therapy" refers to simultaneous administration (administration of two or more therapeutic agents at the same time) and time-different administration (administration of one or more therapeutic agents at a time different from the administration of another therapeutic agent or agents), as long as the therapeutic agents are present in the patient's body to some extent at the same time, preferably in an effective amount. In certain preferred aspects, one or more compounds of the present invention described herein are co-administered in combination with at least one additional bioactive agent (especially including anticancer agents). In particularly preferred aspects, the co-administration of the compounds produces synergistic activity and / or therapy, including anticancer activity.

[0033] Unless otherwise indicated, as used herein, the term "compound" refers to any specific chemical compound disclosed herein, and includes, in the context of the invention, its tautomers, regioisomers, geometric isomers, and (where applicable) stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers), as well as pharmaceutically acceptable salts and derivatives, including prodrugs and / or deuterated forms thereof (where applicable). Deuterated small molecules are contemplated as those in which one or more hydrogen atoms contained in the drug molecule have been replaced with deuterium.

[0034] When used in this context, the term compound generally refers to a single compound, but may also include other compounds, such as stereoisomers, regioisomers and / or optical isomers (including racemic mixtures) and specific enantiomers or enantiomerically enriched mixtures of the disclosed compounds. In this context, the term also refers to a prodrug form of a compound that has been modified to facilitate administration and delivery of the compound to the active site. It should be noted that when describing the compounds of the present invention, a number of substituents and variables associated therewith are described. It will be understood by those of ordinary skill in the art that the molecules described herein are stable compounds as generally described below.

[0035] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, thereby targeting them for degradation. For example, an E3 ubiquitin ligase protein, alone or in combination with an E2 ubiquitin conjugating enzyme, causes ubiquitin to attach to a lysine on a target protein and subsequently targets the specific protein substrate for degradation by the proteasome. Therefore, an E3 ubiquitin ligase, alone or in combination with an E2 ubiquitin conjugating enzyme, is responsible for transferring ubiquitin to the targeted protein. Generally speaking, ubiquitin ligases participate in polyubiquitination, where a second ubiquitin is attached to a first ubiquitin; a third ubiquitin is attached to a second ubiquitin, and so on. Polyubiquitination marks a 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 a ubiquitin ligase. Monoubiquitinated proteins are not targeted for proteasomal degradation, but can alter their cellular localization or function, for example, by binding to other proteins with domains capable of binding ubiquitin. To further complicate matters, different lysines on ubiquitin can be targeted by E3s to generate chains. The most common lysine is Lys48 in the ubiquitin chain. This is the lysine used to prepare polyubiquitin that is recognized by the proteasome.

[0036] 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 popular E3 ligases, recruited by bifunctional proteolysis-targeting chimeras (PROTACs) to induce ubiquitination and subsequent proteasomal degradation of target proteins (Maniaci C. et al., Bioorg Med Chem. 2019, 27(12): 2466-2479).

[0037] As used herein, the term "alkyl," by itself or as part of another substituent, refers to a straight or branched chain hydrocarbon radical having up to twelve carbon atoms, unless otherwise indicated. In some embodiments, the number of carbon atoms specified (i.e., C 1-C8 means one to eight carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Alkyl groups may be optionally substituted as provided herein. In some embodiments, the alkyl group is C 1- C6 alkyl; in some embodiments, the alkyl group is C 1- C4 alkyl.

[0038] When a range of carbon atoms is used herein, such as C1-C6, all ranges as well as individual carbon atom numbers are encompassed. For example, "C1-C3" includes C 1- C3, C 1- C2, C 2- C3, C1, C2 and C3.

[0039] The term "optionally substituted" as used in conjunction with a substituent as defined herein means that the substituent may, but is not required to, have one or more hydrogens replaced with one or more suitable functional groups or other substituents provided herein. For example, a substituent may be optionally substituted with one or more of the following: 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, halogenated (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, 6-12 membered aryl, benzyl, pyridyl, pyrazolyl, thiazolyl, isothiazolyl or other 5-12 membered heteroaryl. In some embodiments, each of the above optional substituents is itself optionally substituted with one or two groups.

[0040] 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)-, where each substituent is independently selected from the optional substituents described herein.

[0041] As used herein, the term "cycloalkyl" refers to a 3-12 membered cyclic alkyl group, and includes bridged rings and spiro rings (e.g., adamantane). Cycloalkyl groups can be fully saturated or partially unsaturated. The term "cycloalkyl" also includes polycondensed ring systems (e.g., ring systems comprising 2, 3, or 4 rings), wherein a single cycloalkyl ring (as defined above) can be fused with one or more groups selected from heterocycles, carbocycles, aryls, or heteroaryls to form polycondensed ring systems. Such polycondensed ring systems can optionally be substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the polycondensed ring carbocycle or heterocycle moieties. When valence requirements allow, the rings of the polycondensed ring systems can be connected to each other via fusion, spiro, and bridge bonds. It should be understood that the individual rings of the polycondensed ring systems can be connected in any order relative to each other. It should also be understood that the attachment point of the polycondensed ring systems (as defined above for cycloalkyl) can 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]heptyl, bicyclo[3.1.1]heptyl, bicyclo[4.1.0]heptyl, spiro[3.3]heptyl, and spiro[3.4]octyl. In some embodiments, the cycloalkyl group is a 3-7 membered cycloalkyl group.

[0042] As used herein, the term "alkenyl" refers to a C 2- C 12 In some embodiments, the alkenyl group is optionally substituted. In some embodiments, the alkenyl group is C 2- C6 alkenyl.

[0043] As used herein, the term "alkynyl" refers to a C 2- C 12 In some embodiments, the alkenyl group is optionally substituted. In some embodiments, the alkynyl group is C 2- C6 alkynyl.

[0044] The terms "alkoxy," "alkylamino," and "alkylthio" are used in their conventional sense and refer to those alkyl groups that are attached to the remainder of the molecule via an oxygen atom ("oxy"), an amino group ("amino"), or a thiol group. The term "alkylamino" includes monoalkylamino and dialkylamino groups, and the alkyl moieties may be the same or different.

[0045] The terms "halo" or "halogen," by themselves or as part of another substituent, mean a fluorine, chlorine, bromine, or iodine atom.

[0046] The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms have been replaced by a heteroatom selected from S, O, P, and N. Exemplary heteroalkyl groups include alkyl ethers, secondary and tertiary alkylamines, alkylamides, alkylsulfides, and the like. The group may be a terminal group or a bridging group. As used herein, when used in the context of a bridging group, a reference to a normal chain refers to a straight chain connecting the atoms at the two terminal positions of the bridging group.

[0047] As used herein, the term "aryl" refers to a single all-carbon aromatic ring or a plurality of fused all-carbon ring systems, wherein at least one ring is aromatic. For example, in certain embodiments, the aryl group has 6 to 12 carbon atoms. The aryl group includes a phenyl group. The aryl group also includes a polycondensed ring system (e.g., a ring system comprising 2, 3, or 4 rings) having about 9 to 12 carbon atoms, wherein at least one ring is aromatic and wherein the other rings may be aromatic or non-aromatic. Such polycondensed ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbocyclic ring portion of the polycondensed ring system. When valence requirements permit, the rings of the polycondensed ring system may be connected to each other via fusion, spiro, and bridge bonds. It should be understood that the attachment point of the polycondensed ring system as defined above may 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-tetrahydronaphthyl, etc.

[0048] As used herein, the term "heteroaryl" refers to a single aromatic ring having at least one atom other than carbon in the ring, wherein such atom is selected from the group consisting of oxygen, nitrogen, and sulfur; "heteroaryl" also includes multiple fused 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. The sulfur and nitrogen atoms may also be present in oxidized form, provided that the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furanyl. "Heteroaryl" also includes polycondensed ring systems (e.g., ring systems containing 2, 3, or 4 rings), wherein, as defined above, the heteroaryl group is fused to one or more rings selected from heteroaryl (forming, for example, naphthyridinyl, such as 1,8-naphthyridinyl), heterocycle (forming, for example, 1,2,3,4-tetrahydronaphthyridinyl, such as 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (forming, for example, 5,6,7,8-tetrahydroquinolinyl), and aryl (forming, for example, indazolyl) to form a polycondensed ring system. Thus, the heteroaryl group (single aromatic ring or multiple condensed ring system) has about 1-20 carbon atoms and about 1-6 heteroatoms within the heteroaryl ring. The heteroaryl group (single aromatic ring or multiple condensed ring system) can also have about 5 to 12 or 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 portion of the condensed ring. When valence requirements permit, the rings of the polycondensed ring system may be connected to each other via fusion, spiro, and bridge bonds. It will be understood that the individual rings of the polycondensed ring system may be connected in any order relative to each other. It will also be understood that the point of attachment of the polycondensed ring system (as defined above for heteroaryl) may be at any position of the heteroaryl ring. It will also be understood that the point of attachment of the heteroaryl or heteroaryl polycondensed ring system may be at any suitable atom of the heteroaryl ring, including carbon atoms and heteroatoms (e.g., nitrogen). Exemplary heteroaryl groups include, but are not limited to, pyridinyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolinylbenzofuranyl, benzimidazolyl, thiazolyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole, and 3b,4,4a,5-tetrahydro-1H-cyclopropyl[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 heteroaryl groups include, but are not limited to, pyridyl, furyl, thiazole, pyrimidine, oxazole, and thiadiazole.

[0049] As used herein, the term "heterocyclyl" or "heterocycle" refers to a single saturated or partially unsaturated ring having at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; the term also includes multiple fused ring systems having at least one such saturated or partially unsaturated ring, which are further described below. Thus, the 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 the sulfur and nitrogen atoms may also exist in their oxidized forms. Exemplary heterocycles include, but are not limited to, azetidinyl, tetrahydrofuranyl and piperidinyl. The term "heterocycle" also includes polycondensed ring systems (e.g., ring systems comprising 2, 3, or 4 rings), wherein a single heterocycle (as defined above) may be fused to one or more groups selected from heterocycles (forming, for example, 1,8-decahydronaphthyridine), carbocycles (forming, for example, decahydroquinoline), and aryl groups to form a polycondensed ring system. Thus, a heterocycle (a single saturated ring or a single partially unsaturated ring or a polycondensed ring system) has about 2-20 carbon atoms and 1-6 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 carbocycle or heterocycle portions of the polycondensed rings. When valence requirements permit, the rings of the polycondensed ring system may be connected to each other via fusion, spiro, and bridge bonds. It should be understood that the individual rings of the polycondensed ring system may be connected in any order relative to each other. Thus, a heterocycle (single saturated ring or single partially unsaturated ring or polycondensed ring system) has about 3-20 atoms within the heterocycle ring system, including about 1-6 heteroatoms. It is also understood that the point of attachment of a polycondensed ring system (as defined above for heterocyclyl) can be at any position of the heterocycle. It is also understood that the point of attachment of a heterocycle or heterocyclic polycondensed ring system can be at any suitable atom of the heterocycle, including carbon atoms and heteroatoms (e.g., nitrogen). In one embodiment, the term heterocycle includes C 2-20 In one embodiment, the term heterocycle includes C 2-7 In one embodiment, the term heterocycle includes C 2-5 In one embodiment, the term heterocycle includes C 2-4Heterocycle. Exemplary heterocycles include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydro-quinolinyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydro-benzofuranyl, 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-pyrrolidine, 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. In one embodiment, the term "heterocycle" refers to a monocyclic, saturated or partially unsaturated 3-8 membered ring having at least one heteroatom. For example, the term includes monocyclic, saturated or partially unsaturated 4, 5, 6 or 7-membered rings having at least one heteroatom. Non-limiting examples of heterocycles include aziridine, azetidine, pyrrolidine, piperidine, piperidine, piperazine, oxirane, morpholine and thiomorpholine. As used herein, the term "9-membered or 10-membered heterobicyclic ring" refers to a partially unsaturated or aromatic fused bicyclic ring system having at least one heteroatom. For example, the term 9-membered or 10-membered heterobicyclic ring includes a bicyclic ring system having a benzo ring fused to a 5-membered or 6-membered saturated, partially unsaturated or aromatic ring containing one or more heteroatoms.

[0050] As used herein, the term "heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si). Where applicable, the nitrogen and sulfur may be in oxidized form.

[0051] As used herein, the term "chiral" refers to molecules that have the property that their mirror image partners are non-superimposable, while the term "achiral" refers to molecules that are superimposable on their mirror image partners.

[0052] As used herein, the term "stereoisomers" refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space, eg, enantiomers, diastereomers, tautomers.

[0053] The term "patient" or "subject" is used throughout the specification to describe an animal, preferably a human or domesticated animal, to whom treatment, including prophylactic treatment, with a composition according to the present disclosure is provided. For treatment of an infection, condition, or disease state specific to a particular animal, such as a human patient, the term patient refers to that particular animal, including domestic animals such as dogs or cats, or farm animals such as horses, cattle, sheep, etc. In general, unless otherwise indicated or implied in the context of the use of the term, in this disclosure, the term patient refers to a human patient.

[0054] The term "effective" is used to describe an amount of a compound, composition, or ingredient that achieves the intended result when used in the context of its intended use. The term effective includes all other effective amount or effective concentration terms otherwise described or used in this application.

[0055] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government or corresponding agency in a country outside the United States, or listed in the US Pharmacopoeia or other generally recognized pharmacopeia for use in animals, such as humans.

[0056] "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. Specifically, such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-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, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or salts formed when an acidic proton present in the parent compound is coordinated with an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. By way of example only, salts also include sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts, tetraalkylammonium salts, etc.; and when the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, such as hydrochlorides, hydrobromides, tartrates, methanesulfonates, acetates, maleates, oxalates, etc.

[0057] A "pharmaceutically acceptable excipient" refers to a nontoxic, biologically tolerable, and otherwise biologically suitable substance for administration to a subject, such as an inert substance, which is added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of the pharmaceutical agent and is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0058] "Solvate" means a physical association of a compound of Formula I with one or more solvent molecules.

[0059] In one embodiment, "treating" or "treatment" of any disease or condition refers to ameliorating the disease or condition (e.g., preventing or reducing the development of at least one of the disease or its clinical symptoms). In another embodiment, "treating" refers to improving at least one physical parameter that may not be discernible by the subject. In yet another embodiment, "treating" refers to regulating the disease or condition physically (e.g., stabilizing a discernible symptom), physiologically (e.g., stabilizing a physical parameter), or both. In yet another embodiment, "treating" refers to delaying the onset of a disease or condition.

[0060] In one aspect, the present disclosure relates to a compound of formula (I):

[0061]

[0062] or a pharmaceutically acceptable salt thereof; wherein

[0063] R1 is halogen, C 1-6 Alkyl or haloalkyl;

[0064] Each R2 is independently H, D or F;

[0065] Each R3 is independently H, D, C 1-6 Alkyl, haloalkyl or C 3-6 Cycloalkyl;

[0066] n is 1, 2, or 3;

[0067] m is 1, 2, 3, 4, 5 or 6;

[0068] R4 is H, D, C 1-6 Alkyl, C 3-6 a cycloalkyl group, an alkoxyalkyl group, a cyanoalkyl group, or a haloalkyl group;

[0069] R5 is H, D or F;

[0070] L1 is a bond, C(R3)2 or CO;

[0071] L2 is a bond, C(R3)2 or CO;

[0072] Ring A1 is a 3-7 membered cycloalkyl group, a 4-7 membered heterocycloalkyl group, an aryl group or a heteroaryl group;

[0073] Ring A2 is a 3-7 membered cycloalkyl group, a 4-7 membered heterocycloalkyl group, an aryl group or a heteroaryl group;

[0074] X1 is CH2CO, CH=CH (when X2=CO) or N=CH (when X2=CO); and

[0075] X2 is CH2CO, CH=CH (when X1=CO) or N=CH (when X1=CO).

[0076] In some embodiments, R in Formula I 1 For halogen, C 1-6 In some embodiments, R in Formula I 1 In some embodiments, R in Formula I 1 C 1-6 In some embodiments, R in Formula I 1 It is a halogenated alkyl group.

[0077] In other embodiments, R in Formula I 1 In other embodiments, R in Formula I 1 In other embodiments, R in Formula I 1 It is a methyl group.

[0078] In some embodiments, each R2 in Formula I is independently H, D, or F. In some embodiments, each R2 in Formula I is H. In some embodiments, each R2 in Formula I is D. In some embodiments, each R2 in Formula I is F.

[0079] In other embodiments, at least one R2 in Formula I is H. In other embodiments, at least one R2 in Formula I is D. In other embodiments, at least one R2 in Formula I is F.

[0080] In some embodiments, n in Formula (I) is 1, 2, or 3. In some embodiments, n in Formula (I) is 1. In other embodiments, n in Formula (I) is 2. In yet other embodiments, n in Formula (I) is 3.

[0081] In some embodiments, each R3 in Formula I is independently H, D, C 1-6 Alkyl, haloalkyl or C 3-6In some embodiments, each R3 in Formula I is H. In some embodiments, each R3 in Formula I is D. In some embodiments, each R3 in Formula I is C 1-6 In some embodiments, each R3 in Formula I is a haloalkyl group. In some embodiments, each R3 in Formula I is a C 3-6 Cycloalkyl.

[0082] In other embodiments, at least one R3 in Formula I is H. In other embodiments, at least one R3 in Formula I is D. In other embodiments, at least one R3 in Formula I is C 1-6 In other embodiments, at least one R3 in Formula I is a haloalkyl group. In other embodiments, at least one R3 in Formula I is a C 3-6 Cycloalkyl.

[0083] In some embodiments, m in Formula (I) is 1, 2, 3, 4, 5, or 6. In some embodiments, m in Formula (I) is 1. In some embodiments, m in Formula (I) is 2. In other embodiments, m in Formula (I) is 3. In other embodiments, m in Formula (I) is 4. In yet other embodiments, m in Formula (I) is 5. In yet other embodiments, m in Formula (I) is 6.

[0084] In some embodiments, R4 in Formula I is H, D, C 1-6 Alkyl, C 3-6 In some embodiments, R4 in Formula I is H. In some embodiments, R4 in Formula I is D. In some embodiments, R4 in Formula I is C 1-6 In other embodiments, R4 in Formula I is a haloalkyl group. In other embodiments, R4 in Formula I is C 3-6 In yet other embodiments, R4 in Formula I is an alkoxyalkyl group. In yet other embodiments, R4 in Formula I is a cyanoalkyl group.

[0085] In some embodiments, R5 in Formula I is independently H, D, or F. In some embodiments, R5 in Formula I is H. In other embodiments, R5 in Formula I is D. In other embodiments, R5 in Formula I is F.

[0086] In some embodiments, L1 in Formula (I) is a bond, C(R3)2, or CO. In some embodiments, L1 in Formula (I) is a bond. In some embodiments, L1 in Formula (I) is C(R3)2. In other embodiments, L1 in Formula (I) is CO. In other embodiments, L1 in Formula (I) is methylene.

[0087] In some embodiments, L2 in Formula (I) is a bond, C(R3)2, or CO. In some embodiments, L2 in Formula (I) is a bond. In some embodiments, L2 in Formula (I) is C(R3)2. In other embodiments, L2 in Formula (I) is CO. In other embodiments, L2 in Formula (I) is methylene.

[0088] In some embodiments, Ring A1 in Formula (I) is a 3-7 membered cycloalkyl group, a 4-7 membered heterocycloalkyl group, an aryl group, or a heteroaryl group.

[0089] In some embodiments, Ring A1 in Formula (I) is a 3-7 membered cycloalkyl. In some embodiments, Ring A1 is a 4-7 membered heterocycloalkyl. In other embodiments, Ring A1 is an aryl. In other embodiments, Ring A1 is a heteroaryl.

[0090] In some embodiments, Ring A1 in Formula (I) is cyclohexyl. In some embodiments, Ring A1 in Formula (I) is piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, azacyclohexanyl, or azabicyclohexanyl.

[0091] In some embodiments, Ring A1 in Formula (I) is piperazinyl. In some embodiments, Ring A1 in Formula (I) is morpholinyl. In other embodiments, Ring A1 in Formula (I) is piperidinyl. In other embodiments, Ring A1 in Formula (I) is pyrrolidinyl. In yet other embodiments, Ring A1 in Formula (I) is azetidinyl. In yet other embodiments, Ring A1 in Formula (I) is azabicyclohexyl.

[0092] In some embodiments, Ring A2 in Formula (I) is a 3-7 membered cycloalkyl, a 4-7 membered heterocycloalkyl, an aryl, or a heteroaryl.

[0093] In some embodiments, Ring A2 in Formula (I) is a 3-7 membered cycloalkyl. In some embodiments, Ring A2 is a 4-7 membered heterocycloalkyl. In other embodiments, Ring A2 is an aryl. In other embodiments, Ring A2 is a heteroaryl.

[0094] In some embodiments, Ring A2 in Formula (I) is cyclohexyl. In some embodiments, Ring A2 in Formula (I) is piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, azacyclohexanyl, or azabicyclohexanyl.

[0095] In some embodiments, Ring A2 in Formula (I) is piperazinyl. In some embodiments, Ring A2 in Formula (I) is morpholinyl. In other embodiments, Ring A2 in Formula (I) is piperidinyl. In other embodiments, Ring A2 in Formula (I) is pyrrolidinyl. In yet other embodiments, Ring A2 in Formula (I) is azetidinyl. In yet other embodiments, Ring A2 in Formula (I) is azabicyclohexyl.

[0096] In some embodiments, X1 in formula (I) is CH2CO, CH=CH (when X2=CO) or N=CH (when X2=CO).

[0097] In some embodiments, X1 in 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).

[0098] In some embodiments, X2 in formula (I) is CH2CO, CH=CH (when X2=CO), or N=CH (when X2=CO).

[0099] In some embodiments, X2 in 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).

[0100] 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.

[0101] In some embodiments, the compound of formula (I) is composed of a compound of formula II

[0102]

[0103] or a pharmaceutically acceptable salt thereof; wherein

[0104] Each R6 is independently H, D, C 1-6 Alkyl, C 3-6 Cycloalkyl or haloalkyl;

[0105] p is 1, 2, 3, 4, 5, 6, 7, or 8; and

[0106] Z is N or CR6; and

[0107] Where each R1, (R2) n 、(R3) m , R4, X1, X2 and ring A2 are defined relative to formula (I).

[0108] In some embodiments, each R6 in Formula II is independently H, D, C 1-6 Alkyl, haloalkyl or C 3-6In some embodiments, each R6 in Formula II is H. In some embodiments, each R6 in Formula II is D. In some embodiments, each R6 in Formula II is C 1-6 In some embodiments, each R6 of Formula II is a haloalkyl group. In some embodiments, each R6 of Formula II is C 3-6 Cycloalkyl.

[0109] In other embodiments, at least one R6 in Formula II is H. In other embodiments, at least one R6 in Formula II is D. In other embodiments, at least one R6 in Formula II is C 1-6 In other embodiments, at least one R6 in Formula II is a haloalkyl group. In other embodiments, at least one R6 in Formula II is a C 3-6 Cycloalkyl.

[0110] In some embodiments, p in Formula II is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, p in Formula II is 1. In some embodiments, p in Formula II is 2. In other embodiments, p in Formula II is 3. In other embodiments, p in Formula II is 4. In other embodiments, p in Formula II is 5. In other embodiments, p in Formula II is 6. In yet other embodiments, p in Formula II is 7. In yet other embodiments, p in Formula II is 8.

[0111] In some embodiments, Z in Formula II is N or CR6. In some embodiments, Z in Formula II is N. In some embodiments, Z in Formula II is CR6. In some embodiments, Z in Formula II is CH3.

[0112] In some embodiments, the compound of formula (I) is composed of a compound of formula III

[0113]

[0114] or a pharmaceutically acceptable salt thereof; and

[0115] Where each R1, (R2) n 、(R3) m , R4, (R6) p , X1 and X2 are defined relative to formula (I) and formula (II).

[0116] In some embodiments, the compound of formula (I) is composed of a compound of formula IV

[0117]

[0118] or a pharmaceutically acceptable salt thereof; and

[0119] Each of R1, R2, (R3) m , R4, (R6) p , X1 and X2 are defined relative to formula (I) and formula (II).

[0120] In some embodiments, the compound of formula (I) is composed of a compound of formula V

[0121]

[0122] or a pharmaceutically acceptable salt thereof; and

[0123] Each of R1, R2, (R3) m , R4 and (R6) p Defined relative to formula (I) and formula (II).

[0124] In some embodiments, the compound of formula (I) is composed of a compound of formula VI

[0125]

[0126] or a pharmaceutically acceptable salt thereof; and

[0127] Where each of R2, R4 and (R6) p Defined relative to formula (I) and formula (II).

[0128] In yet other embodiments, the compound of formula (I) is:

[0129] 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;

[0130] 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-dimethylpiperazin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0131] 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-dimethylpiperazin-1-yl)methyl)morpholino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0132] 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-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0133] 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-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0134] 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;

[0135] 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;

[0136] 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;

[0137] 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;

[0138] 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;

[0139] 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;

[0140] 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;

[0141] 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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0142] 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-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0143] 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-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0144] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0145] (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-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0146] (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-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0147] (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-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0148] 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-dimethylpiperazin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0149] 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-dimethylpiperazin-1-yl)methyl)morpholino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0150] 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-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0151] 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-dimethylpiperazin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0152] 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-dimethylpiperazin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0153] 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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0154] 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;

[0155] 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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0156] 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;

[0157] 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-ethylpiperazin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0158] 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-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0159] 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-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0160] 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;

[0161] 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;

[0162] 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;

[0163] 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;

[0164] 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;

[0165] 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;

[0166] 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;

[0167] 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;

[0168] 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;

[0169] 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-dimethylpiperazin-1-yl)methyl)-3-fluoropiperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0170] 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-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0171] 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;

[0172] 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-dimethylpiperazin-1-yl)methyl)morpholino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0173] 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-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0174] 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)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0175] 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;

[0176] 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;

[0177] 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;

[0178] 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;

[0179] 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;

[0180] 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;

[0181] 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;

[0182] 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;

[0183] 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;

[0184] 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;

[0185] 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;

[0186] 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;

[0187] 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;

[0188] 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;

[0189] 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-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0190] 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]pyridazine-8-carbonyl)-3,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0191] or a pharmaceutically acceptable salt thereof.

[0192] In yet other embodiments, the compound of formula (I) is:

[0193] (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;

[0194] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0195] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0196] (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]pyridazine-8-carbonyl)-2,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0197] 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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0198] 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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0199] (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]pyridazine-8-carbonyl)-2,6-dimethylpiperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0200] (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]pyridazine-8-carbonyl)-2,6-dimethylpiperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0201] (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]pyridazine-8-carbonyl)-2,2-dimethylpiperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0202] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0203] (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]pyridazine-8-carbonyl)-3,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0204] (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)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0205] (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]pyridazine-8-carbonyl)-2,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0206] (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]pyridazine-8-carbonyl)-2,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0207] 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;

[0208] 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;

[0209] 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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0210] 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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0211] 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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0212] 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]pyridazine-8-carbonyl)-2,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0213] 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;

[0214] 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;

[0215] 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;

[0216] 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;

[0217] (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;

[0218] (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;

[0219] 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-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0220] 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-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0221] 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-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0222] ((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;

[0223] ((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;

[0224] (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;

[0225] (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;

[0226] (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;

[0227] (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;

[0228] (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;

[0229] (3S)-3-(6-(4-((4-(2-(3-fluoro-2-hydroxyphenyl)-6a-(trifluoro-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;

[0230] (3S)-3-(6-(4-((4-(2-(3-fluoro-2-hydroxyphenyl)-6a-(trifluoro-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;

[0231] (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]pyridazine-8-carbonyl)-4-fluorocyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0232] (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]pyridazine-8-carbonyl)-4-fluorocyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0233] (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]pyridazine-8-carbonyl)-4-fluoropiperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0234] (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-fluoropiperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0235] (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]pyridazine-8-carbonyl)-4-fluoropiperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0236] (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]pyridazine-8-carbonyl)-4-fluoropiperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0237] (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]pyridazine-8-carbonyl)-4-fluoropiperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0238] (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]pyridazine-8-carbonyl)-4-fluoropiperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0239] (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)piperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0240] (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]pyridazine-8-carbonyl)-4-fluoropiperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0241] (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]pyridazine-8-carbonyl)-4-fluoropiperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0242] 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)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0243] (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;

[0244] 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;

[0245] 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;

[0246] (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;

[0247] (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;

[0248] 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;

[0249] (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;

[0250] (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;

[0251] 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;

[0252] (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]pyridazine-8-carbonyl)-2,2-dimethylpiperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0253] (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]pyridazine-8-carbonyl)-2,2-dimethylpiperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0254] or a pharmaceutically acceptable salt thereof.

[0255] In yet other embodiments, the compound of formula (I) is:

[0256] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0257] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0258] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0259] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0260] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0261] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0262] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0263] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0264] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)morpholino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0265] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)morpholino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0266] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)morpholino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0267] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)morpholino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0268] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0269] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0270] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0271] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0272] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0273] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0274] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0275] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0276] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0277] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0278] (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;

[0279] (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;

[0280] (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;

[0281] (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;

[0282] (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;

[0283] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0284] (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;

[0285] (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;

[0286] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0287] (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;

[0288] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0289] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0290] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0291] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0292] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0293] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0294] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0295] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0296] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0297] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0298] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0299] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0300] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0301] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0302] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0303] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0304] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0305] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0306] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0307] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0308] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0309] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0310] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0311] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0312] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0313] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0314] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0315] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0316] (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]pyridazine-8-carbonyl)-2,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0317] (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]pyridazine-8-carbonyl)-2,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0318] (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]pyridazine-8-carbonyl)-2,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0319] (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]pyridazine-8-carbonyl)-2,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0320] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0321] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0322] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0323] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0324] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0325] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0326] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0327] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0328] (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;

[0329] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0330] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0331] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0332] (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]pyridazine-8-carbonyl)-2,6-dimethylpiperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0333] (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]pyridazine-8-carbonyl)-2,6-dimethylpiperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0334] (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]pyridazine-8-carbonyl)-2,6-dimethylpiperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0335] (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]pyridazine-8-carbonyl)-2,6-dimethylpiperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0336] (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;

[0337] (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;

[0338] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0339] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0340] (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]pyridazine-8-carbonyl)-2,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0341] (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]pyridazine-8-carbonyl)-2,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0342] (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]pyridazine-8-carbonyl)-2,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0343] (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]pyridazine-8-carbonyl)-2,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0344] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0345] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0346] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0347] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0348] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0349] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0350] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0351] (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0352] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0353] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0354] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0355] (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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0356] or a pharmaceutically acceptable salt thereof.

[0357] It will be apparent that compounds of Formula I (including all subgenera described herein) can have multiple stereocenters. Thus, there are multiple stereoisomers (enantiomers and diastereomers) of compounds of Formula I (and subgenera described herein). The present disclosure contemplates and encompasses every stereoisomer of any compound of Formula I (and subgenera described herein), as well as mixtures of such stereoisomers.

[0358] Pharmaceutically acceptable salts and solvates of the compounds of Formula I (including all subgenera described herein) are also within the scope of this disclosure.

[0359] The present disclosure also contemplates isotopic variations of the compounds of Formula I, including all subgenera described herein.

[0360] Pharmaceutical compositions and methods of administration

[0361] The pharmaceutical compositions of the present invention are generally formulated to provide a therapeutically effective amount of a compound of the present disclosure as an active ingredient or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. Where necessary, the pharmaceutical composition contains a pharmaceutically acceptable salt and / or coordination complex thereof and one or more pharmaceutically acceptable excipients, carriers (including inert solid diluents and fillers), diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers and adjuvants.

[0362] Pharmaceutical composition of the present invention can be used alone or in combination with one or more other medicaments, and described other medicaments are also usually used in the form of pharmaceutical composition.When needed, one or more compounds of the present invention and other medicaments can be mixed into preparation, or two components can be formulated into independent preparation so that they are used in combination alone or simultaneously.

[0363] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions of the present invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0. 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 within a range defined by and including any two of the above numbers) w / w, w / v or v / v.

[0364] In some embodiments, the concentration of one or more compounds of the invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.5 0%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25% , 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03 %, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% (or a number within a range defined by and including any two of the above numbers) w / w, w / v or v / v.

[0365] In some embodiments, the concentration of one or more compounds of the invention is between 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 26%, about 0.09% to about 27%, about 0.10% to about 28%, about 0.11% to about 29%, about 0.12% to about 29%, about 0.13% to about 29%, about 0.14% to about 29%, about 0.15% to about 29%, about 0.16% to about 29%, about 0.17% to about 29%, about 0.18% to about 29%, about 0.19% to about 29%, about 0.20% to about 29%, about 0.21% to about 29%, about 0.22% to about 29%, about 0.23% to about 29%, about 0.24% to about 29%, about 0.25% to about 29%, about 0.26% to about 29%, about 0.27% to about 29%, about 0.28% to about 29%, about 0.29% to about 29%, about 0.29% to about 29%, about 0.29% to about 29%, about 0.2 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.

[0366] In some embodiments, the concentration of one or more compounds of the 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.

[0367] In some embodiments, the amount of one or more compounds of the present invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0. 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g or 0.0001g (or a number within a range defined by and including any two of the above numbers).

[0368] In some embodiments, the amount of one or more compounds of the present invention is greater 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, 0.003 5g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.008g ,0.0085g,0.009g,0.0095g,0.01g,0.015g,0.02g,0.025g,0.03g,0.035g,0.04g,0 .045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.095 g, 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g, 0.5g, 0.55g, 0.6g, 0.65g, 0. 7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5, 3g, 3.5, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g or 10g (or a number within the range defined by and including any two of the above numbers).

[0369] In some embodiments, the amount of one or more compounds of the invention ranges from 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.

[0370] The compounds according to the present invention are effective over a wide range of dosages. For example, in the treatment of adults, dosages of 0.01 to 1000 mg per day, 0.5 to 100 mg per day, 1 to 50 mg per day, and 5 to 40 mg per day are examples of dosages that can be used. An exemplary dosage is 10 to 30 mg per day. The exact dosage will depend on the route of administration, the compound administration form, the subject to be treated, the subject's weight to be treated, and the preference and experience of the attending physician.

[0371] The pharmaceutical compositions of the present invention generally contain the active ingredient of the present invention (e.g., a 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, penetration enhancers, solubilizers and adjuvants.

[0372] Non-limiting exemplary pharmaceutical compositions and methods for their preparation are described below.

[0373] Pharmaceutical compositions for oral administration

[0374] In some embodiments, the present invention provides a pharmaceutical composition for oral administration, which contains a compound of the present invention and a pharmaceutical excipient suitable for oral administration.

[0375] 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 pharmaceutical agent; and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further comprises: (iv) an effective amount of a third pharmaceutical agent.

[0376] In some embodiments, the pharmaceutical composition can be a liquid pharmaceutical composition suitable for oral consumption. The pharmaceutical composition of the present invention suitable for oral administration can be presented in discrete dosage forms, such as capsules, cachets or tablets, or each containing a predetermined amount of active ingredients in the form of powders or granules in a liquid or aerosol spray, solution, or suspension in an aqueous or non-aqueous liquid, oil-in-water emulsion or water-in-oil liquid emulsion. Such dosage forms can be prepared by any pharmaceutical method, but all methods include the step of associating the active ingredient with a carrier, which constitutes one or more essential ingredients. Typically, the composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely powdered solid carrier or both, and then forming the product into the desired presentation form if necessary. For example, tablets can be prepared by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing in a suitable machine an active ingredient in a free-flowing form (such as a powder or granule) optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent and / or a surfactant or a dispersant. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0377] The present invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, as water may promote the degradation of some compounds. For example, in the pharmaceutical field, water (e.g., 5%) can be added as a means of simulating long-term storage to determine the properties of the formulation over time, such as shelf life or stability. The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-moisture ingredients and low-moisture or low-humidity conditions. If substantial contact with moisture and / or humidity is expected during manufacture, packaging, and / or storage, the pharmaceutical compositions and dosage forms of the present invention containing lactose can be made water-free. Anhydrous pharmaceutical compositions can be prepared and stored in a manner that maintains the anhydrous nature of the anhydrous pharmaceutical composition. Therefore, anhydrous compositions can be packaged using materials known to prevent exposure to water so that the composition can be included in a suitable prescribed kit. Examples of suitable packaging include, but are not limited to, sealed foils, plastics, etc., unit dose containers, blister packs, and strip packs.

[0378] According to conventional pharmaceutical compounding technology, active ingredient can be closely mixed with pharmaceutical carrier. Carrier can adopt various forms depending on the desired preparation form for administration. When preparing the composition of oral dosage form, in the case of oral liquid preparation (such as suspension, solution and elixir) or aerosol, any commonly used pharmaceutical medium can be used as carrier, such as water, ethylene glycol, oil, alcohol, flavoring agent, preservative, colorant etc.; Or in the case of oral solid preparation, carriers such as starch, sugar, microcrystalline cellulose, diluent, granulating agent, lubricant, binder and disintegrant can be used, and lactose is not used in some embodiments. For example, in the case of solid oral preparation, suitable carrier includes powder, capsule and tablet. If desired, tablet can be coated by standard aqueous or non-aqueous technology.

[0379] Suitable binders for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums (e.g., acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum), cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

[0380] 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, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0381] Disintegrants can be used in the compositions of the present invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much disintegrant may produce tablets that may disintegrate in the bottle. Too little disintegrant may not be sufficient to cause disintegration to occur, and may therefore change the rate and extent of release of one or more active ingredients from the dosage form. Therefore, a sufficient amount of disintegrant (which will not adversely change the release of one or more active ingredients due to too little or too much) can be used to form a dosage form of the compound disclosed herein. The amount of disintegrant used can vary based on the type of formulation and the mode of administration and can be easily discerned by one of ordinary skill in the art. About 0.5 to about 15 weight % disintegrant or about 1 to about 5 weight % disintegrant can be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, or mixtures thereof.

[0382] Lubricants that can be used to form pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerol, 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 a mixture thereof. Additional lubricants include, for example, a condensed aerosol of synthetic silica, synthetic silicon dioxide, or a mixture thereof. Optionally, a lubricant can be added in an amount less than about 1% by weight of the pharmaceutical composition.

[0383] When aqueous suspensions and / or elixirs are required for oral administration, the active ingredient therein may be combined with various sweetening or flavoring agents, coloring agents or dyes and, if desired, emulsifying and / or suspending agents and such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

[0384] Tablets can be uncoated or can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be used. Formulations for oral use can also be presented in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or in the form of soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0385] 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 can be used, a mixture of lipophilic surfactants can be used, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant can be used.

[0386] Suitable hydrophilic surfactants can generally have an HLB value of at least 10, while suitable lipophilic surfactants can generally have an HLB value of about 10 or less. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values ​​are more lipophilic or hydrophobic and have greater solubility in oils, while surfactants with higher HLB values ​​are more hydrophilic and have greater solubility in aqueous solutions.

[0387] Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is generally not applicable. Similarly, lipophilic (e.g., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, the HLB value of a surfactant is only a rough guide that is commonly used to achieve the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0388] The hydrophilic surfactant can be an ionic or nonionic surfactant. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidates; fatty acid derivatives of amino acids, oligopeptides and polypeptides; glyceride derivatives of amino acids, oligopeptides and polypeptides; lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; phospholipids and their derivatives; lysolecithin and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; acyl lactylates; monoacetylated and diacetylated tartaric acid esters of monoglycerides and diglycerides; succinylated monoglycerides and diglycerides; citric acid esters of monoglycerides and diglycerides; and mixtures thereof.

[0389] Within the above group, ionic surfactants include, for example: lecithin, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; acyl lactylations; monoacetylated and diacetylated tartaric acid esters of monoglycerides and diglycerides; succinylated monoglycerides and diglycerides; citric acid esters of monoglycerides and diglycerides; and mixtures thereof.

[0390] Ionic surfactants can be ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, fatty acid lactates, stearoyl-2-lactate, stearoyl lactylate, succinylated monoglycerides, monoacetylated / diacetylated tartaric acid esters of monoglycerides / diglycerides, citrate esters of monoglycerides / diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linolenate, stearate, lauryl sulfate, tetradecyl sulfate, docusate, lauroylcarnitine, palmitoylcarnitine, myristoylcarnitine, and salts and mixtures thereof.

[0391] The hydrophilic nonionic surfactant may include, but is not limited to, alkyl glucosides; alkyl maltosides; alkyl thioglucosides; polyethylene glycol glycerol laurate; polyoxyalkylene alkyl ethers, such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols, such as polyethylene glycol alkylphenols; polyoxyalkylene alkylphenol 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 polyols having at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; polyoxyethylene sterols, derivatives and analogs thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of polyols having 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 sugar.

[0392] 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 triolein, 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 Capric / Caprylic Glycerides, PEG-8 Capric / Caprylic Glycerides, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Phytosterols, PEG-30 Soybean Sterols, PEG-20 Trioleate, PEG-40 Betaine 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-10 oleate, polysorbate 40, polysorbate 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series and poloxamer.

[0393] By way of example only, suitable lipophilic surfactants include: 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 monoglycerides and diglycerides; hydrophobic transesterification products of polyols with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or hydrophobic transesterification products of polyols with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0394] In one embodiment, the composition may include a solubilizing agent to ensure good solubilization and / or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This is especially important for compositions for non-oral use (e.g., compositions for injection). A solubilizing agent may 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 uniform solution or dispersion.

[0395] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, oxyalkyl glycols, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; polyethylene glycol ethers having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycogen) or methoxy PEG; amides and other nitrogen-containing compounds, such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, PEG-1, PEG-2, PEG-3, PEG-4, PEG-5, PEG-6, PEG-7, PEG-8, PEG-9, PEG-10, PEG-11, PEG-12, PEG-13, PEG-14, PEG-15, PEG-16, PEG-17, PEG-18, PEG-19, PEG-20, PEG-21, PEG-22, PEG-23, PEG-24, PEG-25, PEG-26, PEG-27, PEG-28, PEG-29, PEG-30, PEG-31, PEG-32, PEG-33, PEG-34, PEG-35, PEG-36, PEG-37, PEG-38, PEG-39, PEG-40, PEG-51, PEG-52, PEG-63, PEG-74, PEG-85, PEG-19, PEG-11 pyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl 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, monocaprylic acid glyceride, diethylene glycol monoethyl ether and water.

[0396] Mixtures of solubilizing agents can also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methyl pyrrolidone, N-hydroxyethyl pyrrolidone, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, glycogen, oxyalkyl glycol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizing agents include sorbitol, glycerol, triacetin, ethanol, PEG-400, glycogen, and propylene glycol.

[0397] The amount of the solubilizing agent that can be included is not particularly limited.The amount of a given solubilizing agent can be limited to the biologically acceptable amount that those skilled in the art can easily determine.In some cases, it may be advantageous to include the solubilizing agent that exceeds the biologically acceptable amount by a large margin, for example, so that the concentration of the medicine is maximized, wherein before providing compositions to the experimenter, conventional techniques such as distillation or evaporation are used to remove excessive solubilizing agent.Therefore, if present, based on the combined weight of medicine and other excipients, the weight ratio of solubilizing agent can be 10 % by weight, 25 % by weight (50%), 100 % by weight (or about 200 % by weight at the most).If desired, a very small amount of solubilizing agent can also be used, such as 5%>, 2%>, 1%) or even less.Usually, solubilizing agent can exist with an amount of about 1 % by weight to about 100 % by weight, more typically about 5 % by weight to about 25 % by weight.

[0398] The composition may further comprise one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, anti-adherents, defoaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicifiers, flavoring agents, colorants, flavor enhancers, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0399] In addition, acids or bases can be incorporated into the composition to facilitate processing, enhance stability, or achieve other purposes. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS), and the like. Also suitable is the alkali as the salt of pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acid, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acid, formic acid, fumaric acid, gluconic acid, hydroquinonesulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, mercaptoacetic acid, toluenesulfonic acid, uric acid etc.The salt of polyprotic acid can also be used, such as sodium phosphate, disodium hydrogen phosphate and sodium dihydrogen phosphate.When alkali is salt, cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metal, alkaline earth metal etc.Example can include but not limited to sodium, potassium, lithium, magnesium, calcium and ammonium.

[0400] Suitable acid is a pharmaceutically acceptable organic acid or inorganic acid. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, etc. 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, hydroquinonesulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc.

[0401] Pharmaceutical compositions for injection

[0402] In some embodiments, the present invention provides a pharmaceutical composition for injection, which contains a compound of the present invention and a pharmaceutical excipient suitable for injection. The components and amounts of the pharmaceutical agents in the composition are as described herein.

[0403] Forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oily suspensions or emulsions with sesame oil, corn oil, cottonseed oil or peanut oil as well as elixirs, mannitol, dextrose or sterile aqueous solutions and similar pharmaceutical vehicles.

[0404] Aqueous solutions in saline are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol etc. (and their applicable mixtures), cyclodextrin derivatives and vegetable oils can also be adopted. Can, for example, be by using coatings such as lecithin, by maintaining the required particle size in the case of a dispersant and by using a surfactant to maintain suitable fluidity. The prevention of microbial action can be achieved by various antibacterial and antifungal agents (for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal (thimerosal) etc.).

[0405] Sterile injectable solutions are prepared by incorporating the compound of the present invention into an appropriate solvent as needed along with the various other ingredients listed above in the desired amount, followed by filtration sterilization. Typically, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle containing the base dispersion medium and the desired other ingredients from the ingredients listed above. In the case of sterile powders for the preparation of sterile injectable solutions, some desirable preparation methods are vacuum drying and freeze drying techniques that produce a powder of the active ingredient and any additional desired ingredients from a previously sterile filtered solution thereof.

[0406] Pharmaceutical compositions for topical (eg, transdermal) delivery

[0407] In some embodiments, the present invention provides a pharmaceutical composition for transdermal delivery, comprising a compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery.

[0408] The compositions of the present invention can be formulated into solid, semisolid or liquid preparations suitable for local or topical administration, such as gels, water-soluble colloids, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, solutions based on dimethyl sulfoxide (DMSO). Typically, carriers with higher densities can provide areas that are exposed to the active ingredient for extended periods of time. In contrast, solution formulations can expose the active ingredient more directly to the selected area.

[0409] The pharmaceutical composition may also comprise a suitable solid or gel phase carrier or excipient which is a compound that increases the penetration of the therapeutic molecule across the stratum corneum permeability barrier of the skin or aids in the delivery of the therapeutic molecule across the stratum corneum permeability barrier of the skin. Many such penetration enhancing molecules are known to those trained in the art of topical formulations.

[0410] 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), pyrrolidones, glyceryl monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[0411] Another exemplary formulation used in the methods of the present invention employs a transdermal delivery device ("patch"). Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound of the present invention in controlled amounts, with or without another pharmaceutical agent.

[0412] The construction and use of transdermal patches for delivering medicaments are well known in the art. See, for example, U.S. Patents 5,023,252, 4,992,445, and 5,001,139. ​​Such patches can be configured to deliver medicaments continuously, pulsed, or on-demand.

[0413] Pharmaceutical compositions for inhalation

[0414] 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 composition is administered via the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be aerosolized using an inert gas. Nebulized solutions may be inhaled directly from a nebulizing device, or the nebulizing device may be attached to a face mask tampons or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0415] Other pharmaceutical compositions

[0416] Pharmaceutical compositions can 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, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G., eds., Handbook of Clinical Drug Data, 10th ed., McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, 3rd ed., Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, 9th ed., McGraw-Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, 10th ed., McGraw-Hill, 2001; Remington's Pharmaceutical Sciences, 13th ed., Sciences, 20th ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, 32nd ed. (The Pharmaceutical Press, London, 1999); all references are incorporated herein by reference in their entirety.

[0417] The administration of the compound or pharmaceutical composition of the present invention can be achieved by any method capable of delivering the compound to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), local (e.g., transdermal application), rectal administration, local delivery by catheter or stent, or by inhalation. The compound can also be administered intrafatally or intrathecally.

[0418] In some embodiments, the compounds or pharmaceutical compositions of the present invention are administered by intravenous injection.

[0419] The amount of the compound administered will depend on the severity of the subject being treated, the disease or condition, the rate of administration, the disposal of the compound and the judgment of the prescribing physician. However, whether in a single dose or in divided doses, the effective dose is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably in the range of about 1 to about 35 mg / kg / day. For a 70 kg person, this will be equivalent to about 0.05 to 7 g / day, preferably about 0.05 to about 2.5 g / day. In some cases, the dosage level below the lower limit of the above range may exceed sufficient amount, and in other cases, another larger dosage can be adopted without causing any harmful side effects, such as by dividing such a larger dose into several small doses for full-day administration.

[0420] In some embodiments, the compounds of the invention are administered in a single dose.

[0421] Typically, such administration will be by injection, such as intravenous injection, to quickly introduce the agent. However, other routes may be used as appropriate. A single dose of a compound of the invention may also be used to treat acute conditions.

[0422] In some embodiments, the compounds of the present invention are administered in multiple doses. Can be administered about once a day, twice a day, three times a day, four times a day, five times a day, six times a day or more than six times a day. Can be administered about once a month, once every two weeks, once a week or once every other day. In another embodiment, the compounds of the present invention and another medicament are administered together about once a day to about 6 times a day. In another embodiment, the administration of the compounds of the present invention and the medicament continues for less than about 7 days. In another embodiment, administration continues for more than about 6 days, 10 days, 14 days, 28 days, two months, six months or one year. In some cases, continuous administration is achieved, and continuous administration continues for the required duration.

[0423] The administration of the compounds of the present invention can continue for the desired duration. In some embodiments, the administration of the compounds of the present invention continues for more than 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days or 28 days. In some embodiments, the administration of the compounds of the present invention continues for less than 28 days, 14 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day. In some embodiments, the compounds of the present invention continue for long-term administration, for example to treat chronic effects.

[0424] An effective amount of the compounds of the present invention can be administered in single or multiple doses by any of the recognized modes of administration having similar utility, including rectal, buccal, intranasal and transdermal routes, by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically or as an inhalant.

[0425] The compositions of the present invention can also be delivered by impregnation or coating devices (e.g., stents) or arterial insert cylindrical polymers. Such methods of administration can, for example, help prevent or improve restenosis after surgeries such as balloon angioplasty. Without being bound by theory, the compounds of the present invention can slow down 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, for example, be administered by local delivery from the cover or sheath of a support, stent graft, graft or stent. In certain embodiments, the compounds of the present invention are mixed with a matrix. Such a matrix can be a polymer matrix and can be used to combine the compound with the support. The polymer matrix suitable for this purpose comprises for example lactone polyester or copolyester, such as polylactide, polycaprolactone glycolide (polycaprolactonglycolide), polyorthoester, polyanhydride, polyamino acid, polysaccharide, polyphosphazene, poly (ether-ester) copolymer (for example, PEO-PLLA), polydimethylsiloxane, poly (ethylene-vinyl acetate), acrylic ester polymer or copolymer (for example, polyhydroxyethyl methyl methacrylate, polyvinyl pyrrolidone), fluorinated polymer (such as polytetrafluoroethylene and cellulose ester). Suitable matrix can be non-degradable or can degrade over time, thereby releasing one or more compounds. The compound of the present invention can be applied to the surface of support by various methods (such as dip coating / spin coating, spray coating, dip coating and / or brush coating). The compound can be applied in a solvent, and solvent evaporation can be allowed, thereby forming a compound layer on support. Alternatively, the compound can be positioned in the main body of support or graft, such as in microchannel or micropore. When implanted, the compound diffuses out from the main body of support to contact with the arterial wall. Such stents can be prepared by immersing a stent manufactured to contain such micropores or microchannels in a solution of the compound of the present invention in a suitable solvent and then evaporating the solvent. Excess drug on the surface of the stent can be removed by another short solvent wash. In yet other embodiments, the compound of the present invention can be covalently linked to the stent or graft. Covalent linkers can be used that degrade in vivo, thereby releasing the compound of the present invention. Any biologically unstable connection, such as ester, amide or anhydride connection, can be used for such purposes. In addition, the compound of the present invention can be administered intravascularly from the balloon used during angioplasty. Extravascular administration of the compound can also be performed by pericardial or adventitial application of the formulation of the present invention to reduce restenosis.

[0426] For example, various stent devices that can be used as described are disclosed in the following references, all of which are hereby incorporated 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.

[0427] The compounds of the present invention can be administered in doses. It is known in the art that, due to the variability in the pharmacokinetics of compounds between subjects, individualization of the dosing regimen is necessary for optimal therapy. The administration of the compounds of the present invention can be found by routine experimentation according to the present disclosure.

[0428] When the compound of the invention is administered as a composition containing one or more agents with a shorter half-life than the compound of the invention, the unit dosage form of the agent and compound of the invention may be adjusted accordingly.

[0429] The pharmaceutical composition of the present invention can be, for example, suitable for oral administration in the form of tablets, capsules, pills, powders, sustained-release formulations, solutions, suspensions, suitable for parenteral administration in the form of sterile solutions, suspensions or emulsions, suitable for topical administration in the form of ointments or creams, or suitable for rectal administration in the form of suppositories. The pharmaceutical composition can be in a unit dosage form suitable for single administration of precise doses. The pharmaceutical composition will comprise conventional pharmaceutical carriers or excipients and the compound of the present invention as an active ingredient. In addition, the pharmaceutical composition may comprise other medicaments (medicinal agent or pharmaceutical agent), carriers, adjuvants, etc.

[0430] Exemplary parenteral administration forms include solutions or suspensions of the active compound in sterile aqueous solutions, for example, aqueous propylene glycol or aqueous dextrose. Such dosage forms can be suitably buffered, if desired.

[0431] How to use

[0432] The method generally comprises administering a therapeutically effective amount of the compound of the present invention to the subject. The therapeutically effective amount of the compound combination of the present invention can be based on the intended application (in vitro or in vivo) or the subject being treated and the condition (e.g., the subject's weight and age, the severity of the condition, mode of administration, etc.) that can be easily determined by those of ordinary skill in the art and change. The term is also applicable to the dosage of inducing a specific response (e.g., the proliferation of the target protein is reduced or the activity is lowered) in the target cell. The specific dosage will change according to the specific compound selected, the dosage regimen followed, whether it is administered in combination with other compounds, administration timing, administration tissue, and the physical delivery system carried by it.

[0433] In certain embodiments, the present invention provides a pharmaceutical composition comprising a bispecific compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0434] In certain embodiments, the present invention provides a pharmaceutical composition comprising a bispecific compound for use in degrading a target protein in a cell.

[0435] In certain embodiments, a method of degrading a target protein comprises administering to a cell a therapeutically effective amount of a bispecific compound or a pharmaceutically acceptable salt thereof, wherein the compound effectively degrades the target protein.

[0436] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of the bispecific formula for use in treating or preventing a disease or condition in which SMARCA2 and / or SMARCA4 plays a role.

[0437] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of the bispecific formula for use in treating or preventing a disease or condition in which SWI / SNF mutations play a role.

[0438] In certain embodiments, the target protein is SMARCA2, SMARCA4, and / or PB1.

[0439] In certain embodiments, the target protein complex is SWI / SNF in a cell.

[0440] In certain embodiments, the disease or condition dependent on SMARCA2 or SMARCA4 comprises cancer.

[0441] In certain embodiments, the disease or disorder dependent on the SWI / SNF complex comprises cancer.

[0442] Exemplary cancers that can be treated by the compounds of the present invention, alone or in combination with at least one additional anticancer agent, include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular and renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, and stomach cancer; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative disorders; sarcomas, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, and leukemia. sarcoma), liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, and schwannoma; intestinal 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.

[0443] In certain embodiments, cancers that can be treated using the compounds according to the present disclosure include, for example, T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-B ALL, pre-B lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, and Philadelphia chromosome-positive CML.

[0444] In certain other embodiments, the cancer is a SMARCA2 and / or SMARAC4 dependent cancer.

[0445] In certain embodiments, the present invention provides a pharmaceutical composition comprising a bispecific compound for use in a disease or condition dependent on SMARCA2 and / or SMARCA4, wherein the disease or condition is cancer.

[0446] The compounds of the present disclosure and pharmaceutical compositions comprising the compounds can be administered alone or in combination with medical therapies to treat any of the described diseases. Medical therapies include, for example, surgery and radiation therapy (e.g., gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, systemic radioisotopes).

[0447] In other aspects, the compounds of the present disclosure, and pharmaceutical compositions containing the compounds, can be administered alone or in combination with one or more other agents to treat any of the described diseases.

[0448] In other methods, the compounds of the present disclosure, and pharmaceutical compositions comprising the same, can be administered in combination with agonists of nuclear receptor agents.

[0449] In other methods, the compounds of the present disclosure, and pharmaceutical compositions containing the compounds, can be administered in combination with antagonists of nuclear receptor agents.

[0450] In other methods, the compounds of the present disclosure, and pharmaceutical compositions containing the compounds, can be administered in combination with an anti-proliferative agent.

[0451] Combination therapy

[0452] In order to treat cancer and other proliferative diseases, the compounds of the present invention can be used in combination with chemotherapeutics, agonists or antagonists of nuclear receptors or other antiproliferative agents. The compounds of the present invention can also be used in combination with medical therapies such as surgery or radiotherapy, for example gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy and systemic radioisotopes. Examples of suitable chemotherapeutic agents include any of the following: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, all-trans retinoic acid, hexamethylmelamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bendamustine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib, intravenous busulfan, intravenous, oral busulfan, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citratecitrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetateacetate), levamisole, lomustine, meclorethamine, megestrolacetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone, phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate disodium, dronate), panobinostat, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib malate maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinstat, and zoledronate.

[0453] In certain embodiments, the compound of the present invention can be used in combination with the therapeutic agent of targeting epigenetic regulator.The example of epigenetic regulator includes bromodomain inhibitors, histone lysine methyltransferase inhibitors, histone arginine methyltransferase inhibitors, histone demethylase inhibitors, histone deacetylase inhibitors, histone acetylase inhibitors and DNA methyltransferase inhibitors.Histone deacetylase inhibitors include, for example, vorinostat.Histone arginine methyltransferase inhibitors include inhibitors of protein arginine methyltransferase (PRMT) such as PRMT5, PRMT1 and PRMT4.DNA methyltransferase inhibitors include inhibitors of DNMT1 and DNMT3.

[0454] For the treatment of cancer and other proliferative diseases, the compounds of the present invention can be used in combination with targeted therapies, comprising JAK kinase inhibitors (e.g., ruxolitinib), PI3 kinase inhibitors (including PI3K-δ selective and broad-spectrum PI3K inhibitors), MEK inhibitors, cyclin-dependent kinase inhibitors (including CDK4 / 6 inhibitors and CDK9 inhibitors), BRAF inhibitors, mTOR inhibitors, proteasome inhibitors (e.g., bortezomib, carfilzomib), 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.

[0455] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, such as 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 an immune checkpoint molecule is an inhibitor of PD-L1, such as 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 an immune checkpoint molecule is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab.

[0456] In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulator. 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 immunomodulator is lenalidomide (LEN) or pomalidomide (POM).

[0457] The compounds of the present invention can be prepared using a variety of preparative reactions known in the literature. The following scheme provides general guidance on preparing the compounds of the present invention. Those skilled in the art will appreciate that the preparations shown in the schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the present invention. Exemplary synthetic methods for preparing the compounds of the present invention are provided in the following schemes.

[0458] The following examples are provided to illustrate some of the concepts described within this disclosure.While the examples are considered to provide embodiments, they should not be considered to limit the more general embodiments described herein.

[0459] Examples

[0460] General synthetic procedure

[0461] The compounds described herein can be prepared according to the following synthetic schemes and general synthetic procedures.

[0462] Solution 1

[0463]

[0464] Compounds of formula (1-8) wherein R4 = H can be prepared according to the route described in Scheme 1. In the presence of a base (e.g., Cs2CO3, NaHCO3, DIPEA), the S reaction between commercially available starting material 1-1 (wherein R4 = H) and compound 1-2 (wherein Q1 = Cl, Br) is carried out at elevated temperature. N Ar reaction gives alcohol 1-3. After treatment with PPh3 / DIAD / DPPA, compound 1-3 is azidated to give compound 1-4. After treatment with PPh3 at high temperature, compound 1-4 is subjected to Staudinger reduction, followed by S in the presence of a base (e.g., Cs2CO3, NaHCO3, DIPEA). N Ar, to give compound 1-5. Protecting the -NH group with an appropriate group (e.g., Boc, SEM, Bn, etc.) can give compound 1-6, which can be converted to compound 1-7 using an appropriate boronic acid or ester (e.g., 2-hydroxy-phenylboronic acid) under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as, but not limited to, tetrakis(triphenylphosphine)palladium(0) or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexed with dichloromethane and a base (e.g., a carbonate base)). Removal of the protecting group can give compound 1-8.

[0465] Option 2

[0466]

[0467] Compounds of formula (1-8) wherein R4≠H can be prepared according to the route described in Scheme 2. Protection of the -NH group of commercially available starting material 2-1 with an appropriate group (e.g., Boc, SEM, Bn, etc.) can provide compound 2-2. Compound 2-2 is esterified in the presence of a base (e.g., Cs2CO3, NaHCO3, DIPEA) to provide compound 2-3. After sequential treatment with LiHMDS and an electrophilic reagent (e.g., MeI), alkylation of compound 2-3 produces compound 2-4 wherein R4≠H. One-pot amide formation, selective deprotection, and S-terminus reaction between compound 2-4 and compound 2-5 (wherein Q1=Cl, Br) in the presence of a base (e.g., Cs2CO3, NaHCO3, DIPEA) at elevated temperature. N Ar affords compound 2-6. Compound 2-6 can be converted to compound 2-7 using a suitable boronic acid or ester (e.g., 2-hydroxy-phenylboronic acid) under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as, but not limited to, tetrakis-(triphenylphosphine)palladium(0) or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexed with dichloromethane and a base (e.g., a carbonate base). Compound 2-7 is reduced in the presence of BH₃…THF at elevated temperature to afford compound 2-8. Removal of the protecting group affords compound 1-8.

[0468] Option 3

[0469]

[0470] Intermediates of formula 3-6 wherein X1 = CO and X2 = CH2 can be synthesized according to the pathway described in Scheme 3. S between 3-1 and 3-2 (e.g., DIPEA) N Ar can provide compound 3-3. Reduction of the cyano group in 3-3 can be achieved under appropriate conditions (eg, Raney Nickel) to give 3-4. Reductive amination and cyclization of 3-4 with 3-5 (eg, DIPEA followed by AcOH and sodium triacetoxyborohydride) gives 3-6, wherein A2 and R5 are as defined above.

[0471] Option 4

[0472]

[0473] Intermediates of formula 3-6 wherein X1 = CH2 and X2 = CO can be synthesized according to the pathway described in Scheme 4. The S between 4-1 and 3-2 (e.g., DIPEA) N Ar can provide compound 4-2. Reduction of the cyano group in 4-2 can be achieved under appropriate conditions (eg, Raney nickel) to give 4-3. Reductive amination and cyclization of 4-3 with 3-5 (eg, DIPEA followed by AcOH and sodium triacetoxyborohydride) gives 3-6, wherein A2 and R5 are as defined above.

[0474] Option 5

[0475]

[0476] Intermediates of formula 3-6 wherein X1 = CO and X2 = CO can be synthesized according to the pathway described in Scheme 5. The S between 5-1 and 3-2 (e.g., DIPEA) N Ar can provide compound 3-6, wherein A2 and R5 are as defined above.

[0477] Option 6

[0478]

[0479] Compounds of formula (I) can be prepared according to the routes described in Scheme 6. Coupling between 1-8 and 6-1 can provide compound 6-2 via urea formation (e.g., DIPEA), amide formation (e.g., HATU), or reductive amination (e.g., sodium triacetoxyborohydride). 6-2 is then coupled with 3-6 (X1, X2 = CH2 or CO) via reductive amination (e.g., sodium triacetoxyborohydride) or alkylation (e.g., DIPEA) to provide compounds of formula (I).

[0480] 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

[0481]

[0482] Step 1: (R)-tert-Butyl 4-(3,6-dichloropyridazin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate

[0483]

[0484] To a solution of 3,4,6-trichloropyridazine (5.70 g, 31.1 mmol) in DMF (24.0 mL) was added N,N-diisopropylethylamine (5.95 mL, 34.2 mmol) and (R)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (7.10 g, 32.8 mmol). The reactants were stirred at 80 ° C overnight. The reactants were cooled to 45 ° C and water (17.0 mL) was slowly added. The resulting clear solution was stirred at 35 ° C for 30 min until a precipitate was formed. Another portion of water (23.0 mL) was slowly added, and the mixture was stirred at 0 ° C for another 1 h. The mixture was filtered, and the resulting solid was washed with water, collected and dried in vacuo to give (R)-4-(3,6-dichloropyridazine-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (8.50 g, 75% yield) as an off-white solid. 14 H 21 LCMS calculated value of Cl2N4O3 [M+H] + :m / z=363.1; Found: 363.1.

[0485] Step 2: (R)-tert-Butyl 3-(azidomethyl)-4-(3,6-dichloropyridazin-4-yl)piperazine-1-carboxylate

[0486]

[0487] To a solution of (R)-4-(3,6-dichloropyridazin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (5.45 g, 15.0 mmol) and triphenylphosphine (4.72 g, 18.0 mmol) in THF (150 mL) was added diisopropyl azodicarboxylate (3.54 mL, 18.0 mmol) and diphenylphosphoryl azide (3.90 mL, 18.0 mmol) at 0 ° C. The reactants were then stirred at room temperature overnight. The reaction mixture was cooled to 0 ° C., quenched with water and extracted with EtOAc. The combined organic layers were washed with saturated brine solution and water, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give crude (R)-3-(azidomethyl)-4-(3,6-dichloropyridazin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (19.4 g), which was used without further purification (30% purity by LCMS). C 14 H 20 LCMS calculated for Cl2N7O2 [M+H] + :m / z=388.1; Found: 388.0.

[0488] Step 3: (S)-tert-Butyl 2-chloro-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazine-8-carboxylate

[0489]

[0490] Triphenylphosphine (4.94 g, 18.8 mmol) was added to a stirred solution of crude (R)-3-(azidomethyl)-4-(3,6-dichloropyridazin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (20.3 g, 15.7 mmol, 30% purity) in THF (200 mL). The resulting solution was stirred at 60 ° C for 3 hours. Water (20.0 mL) and N, N-diisopropylethylamine (8.20 mL, 47.1 mmol) were added sequentially. After 20 hours, the reaction mixture was diluted with EtOAc (100 mL) and water (100 mL). The aqueous layer was separated and extracted with EtOAc. The combined organic layer was washed with a saturated brine solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a gradient of 0-100% EtOAc / hexanes to afford (S)-tert-butyl 2-chloro-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (3.10 g, 60% yield) as an off-white solid. 14 H 21 LCMS calculated for ClN5O2 [M+H] + :m / z=326.1; found: 326.2.

[0491] Step 4: (R)-di-tert-butyl 2-chloro-6a,7,9,10-tetrahydro-5H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate

[0492]

[0493] To a stirred solution of (S)-2-chloro-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazine-8-carboxylic acid tert-butyl ester (3.10 g, 9.52 mmol) in DCM (120 mL) was added di-tert-butyl dicarbonate (6.23 g, 28.6 mmol) and 4-(dimethylamino)pyridine (1.16 g, 9.52 mmol) at room temperature. After 1 hour, the reactant was diluted with DCM (120 mL) and saturated aqueous solution of NH4Cl (50.0 mL). After another 1 hour, the aqueous layer was separated and extracted with DCM. The organic layers were combined, washed with saturated brine solution, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with 50% EtOAc / hexanes to afford (R)-di-tert-butyl 2-chloro-6a,7,9,10-tetrahydro-5H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate (3.90 g, 96% yield). 19 H 29 LCMS calculated for ClN5O4 [M+H] + :m / z=426.2; found: 426.3.

[0494]

[0495] Step 5: (R)-di-tert-butyl 2-(3-fluoro-2-hydroxyphenyl)-6a,7,9,10-tetrahydro-5H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate

[0496] A mixture of (R)-di-tert-butyl 2-chloro-6a,7,9,10-tetrahydro-5H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate (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) was degassed. After the addition of 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 condensed. The mixture was purified by flash column chromatography on silica gel eluting with a gradient of 0-45% EtOAc / hexanes to afford (R)-di-tert-butyl 2-(3-fluoro-2-hydroxyphenyl)-6a,7,9,10-tetrahydro-5H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate (1.10 g, 78% yield). 25 H 33 LCMS calculated value of FN5O5 [M+H]+: m / z=502.3; found: 502.1.

[0497] 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

[0498] A 4N solution of HCl in 1,4-dioxane (4.00 mL) was added dropwise to a solution of (R)-di-tert-butyl 2-(3-fluoro-2-hydroxyphenyl)-6a,7,9,10-tetrahydro-5H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate (1.10 g, 2.12 mmol) in DCM (10.0 mL). The reaction was stirred at room temperature for 5 hours. 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. 15 H 17 LCMS calculated value [M+H]+ for FN5O: m / z=302.1; found: 302.0.

[0499] 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

[0500]

[0501] The title compound was prepared using a procedure analogous to that described for Intermediate 1, substituting (3,5-difluoro-2-hydroxyphenyl)boronic acid for (3-fluoro-2-hydroxyphenyl)boronic acid in Step 5. 15 H 16 LCMS calculated value of F2N5O [M+H]+: m / z=320.1; found value: 320.0

[0502] 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

[0503]

[0504] Step 1: O-Benzyl-N-(tert-butoxycarbonyl)-L-seryl-L-alanine methyl ester

[0505]

[0506] To a stirred suspension of O-benzyl-N-(tert-butoxycarbonyl)-L-serine (20.0 g, 67.7 mmol) and 1-hydroxybenzotriazole hydrate (11.0 g, 81.3 mmol) in DCM (451 mL) at 0° C. was added N,N-diisopropylethylamine (14.2 mL, 81.3 mmol). 1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (15.6 g, 81.3 mmol) was added to the reaction mixture and stirred at 0° C. for 15 minutes. A solution of alanine methyl ester hydrochloride (11.3 g, 81.3 mmol) and N,N-diisopropylethylamine (14.2 mL, 81.3 mmol) in DMF (30 mL) was added dropwise at 0° C. over 5 minutes. The reaction was allowed to warm to room temperature and stirred for 3 hours. Water (500 mL) was added, and the aqueous phase was extracted with DCM (300 mL x 3). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography eluting with a gradient of 0-100% EtOAC / hexane to provide O-benzyl-N-(tert-butoxycarbonyl)-L-seryl-L-alanine methyl ester (26.1 g, 99.0% yield). 19 H 29 LCMS calculated value of N2O6 (M+H) + :m / z=381.2; found: 381.0.

[0507] Step 2: O-Benzyl-L-seryl-L-alanine methyl ester

[0508]

[0509] To a solution of O-benzyl-N-(tert-butoxycarbonyl)-L-seryl-L-alanine methyl ester (26.1 g, 68.6 mmol) in DCM (260 mL) was added TFA (51.4 mL, 672 mmol) at room temperature. The reactant was stirred for 3 hours. The reaction mixture was basified to between pH 7 and pH 8 by a saturated aqueous solution of NaHCO . The aqueous phase was extracted with DCM (100 mL × 3) and the organic matter was washed with a saturated brine solution (100 mL × 1). The combined organic phases were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was used directly in the next step without further purification to give crude O-benzyl-L-seryl-L-alanine methyl ester (16.9 g). 14 H 21 LCMS calculated value of N2O4 (M+H) + :m / z=281.2; found: 281.0.

[0510] Step 3: (3S,6S)-3-((Benzyloxy)methyl)-6-methylpiperazine-2,5-dione

[0511]

[0512] A solution of crude O-benzyl-L-seryl-L-alanine methyl ester (16.9 g, 60.3 mmol) in 1,4-dioxane (169 mL) was stirred at 100 ° C overnight. The reaction was cooled to room temperature, after which a white solid precipitated. The white precipitate was collected by filtration and washed with cold MTBE (100 mL) to give (3S, 6S)-3-((benzyloxy)methyl)-6-methylpiperazine-2,5-dione (11.0 g, yield: 73.0% yield). 13 H 17 LCMS calculated value of N2O3 (M+H) + :m / z=249.1; found: 249.2.

[0513] Step 4: (2R,5S)-2-((Benzyloxy)methyl)-5-methylpiperazine

[0514]

[0515] To a solution of (3S, 6S) -3- ((benzyloxy) methyl) -6- methylpiperazine -2,5- dione (9.00 g, 36.3 mmol) in THF (201 mL) was added borane dimethyl sulfide complex (27.5 mL, 290 mmol) on an ice-water bath. The reactants were warmed to room temperature and stirred at 60 ° C overnight. The reactants were cooled on an ice-water bath and MeOH (200 mL) was slowly added. The reaction mixture was warmed to room temperature and a 1N HCl aqueous solution was added dropwise to reach a pH of about 3. The mixture was stirred at 50 ° C for 3 hours. The reaction mixture was basified to pH 12 by dropwise addition of a 1N NaOH aqueous solution, and the aqueous phase was extracted with CHCl (200 mL × 3). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was used directly in the next step without further purification to give crude (2R,5S)-2-((benzyloxy)methyl)-5-methylpiperazine (9.80 g). 13 H 21 LCMS calculated for N2O (M+H) + :m / z=221.2; Found: 221.2.

[0516] Step 5: ((2R,5S)-5-methylpiperazin-2-yl)methanol

[0517]

[0518] To a solution of crude (2R, 5S)-2-((benzyloxy)methyl)-5-methylpiperazine (9.80, 44.5mmol) in DCM (445mL) was added a 1M solution of BCl3 (178mL, 178mmol) in DCM at -78°C. The reactants were slowly warmed to room temperature and stirred overnight. The reactants were cooled on an ice-water bath and MeOH (200mL) was slowly added. The reaction mixture was concentrated to dryness under reduced pressure. The residue was used directly in the next step without further purification to give crude ((2R, 5S)-5-methylpiperazine-2-yl)methanol (9.0g). CH 15 LCMS calculated for N2O (M+H) + :m / z=131.1; found: 131.0.

[0519] Step 6: Di-tert-butyl (2R,5S)-2-(hydroxymethyl)-5-methylpiperazine-1,4-dicarboxylate

[0520]

[0521] To a solution of crude ((2R,5S)-5-methylpiperazin-2-yl)methanol (9.00 g, 69.1 mmol) in DCM (376 mL) was added triethylamine (120 mL, 864 mmol) and di-tert-butyl dicarbonate (45.3 g, 207 mmol) at 0°C. The reaction was stirred at room temperature overnight and then concentrated to dryness under reduced pressure. The residue was used directly in the next step without further purification to give crude di-tert-butyl (2R,5S)-2-(hydroxymethyl)-5-methylpiperazine-1,4-dicarboxylate (24.0 g). 16 H 31 LCMS calculated value of N2O5 (M+H) + :m / z=331.2; found: 331.0.

[0522] Step 7: tert-Butyl (2S,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate

[0523]

[0524] To a solution of crude (2R, 5S)-2-(hydroxymethyl)-5-methylpiperazine-1,4-dicarboxylic acid di-tert-butyl ester (14.0 g, 42.4 mmol) in EtOH (78.5 mL) was added a solution of NaOH (8.50 g, 212 mmol) in water (78.5 mL). The reaction mixture was stirred at 80 ° C overnight. The reactants were cooled to room temperature and the pH was about 9 by dropwise addition of 1N HCl aqueous solution. The aqueous phase was extracted with CHCl3 (100 mL×3), and the combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash silica gel column chromatography with a gradient elution of 0-10% DCM / MeOH (containing 0.1% triethylamine) to give (2S, 5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (2.70 g, 28% yield). 11 H 23 LCMS calculated value of N2O3 (M+H) + :m / z=231.2; found: 231.1.

[0525] Step 8: tert-Butyl (2S,5R)-4-(3,6-dichloropyridazin-4-yl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate

[0526]

[0527] To a solution of 3,4,6-trichloropyridazine (406 mg, 2.21 mmol) in DMF (1.75 mL) was added NN-diisopropylethylamine (0.59 mL, 3.39 mmol) and DMF (1.75 mL) containing (2S,5R)-5-(hydroxy-methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (300 mg, 1.30 mmol) at room temperature. The reaction was stirred at 80 ° C overnight. The reaction was cooled to room temperature, diluted with water (15.0 mL) and extracted with EtOAc (15 mL × 3). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with a gradient of 10-100% EtOAc / heptane to afford tert-butyl (2S,5R)-4-(3,6-dichloropyridazin-4-yl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate (408 mg, 83% yield) as a yellow viscous oil. 15 H 23 LCMS calculated value of Cl2N4O3 [M+H] + :m / z=377.1; found: 377.0.

[0528] Step 9: tert-Butyl (2S,5R)-5-(azidomethyl)-4-(3,6-dichloropyridazin-4-yl)-2-methylpiperazine-1-carboxylate

[0529]

[0530] To a solution of (2S,5R)-4-(3,6-dichloropyridazin-4-yl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (2.70 g, 7.16 mmol) and triphenylphosphine (2.63 g, 10 mmol) in THF (35 mL) was slowly added diisopropyl azodicarboxylate (1.97 mL, 10 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 10 minutes, after which diphenylphosphoryl azide (2.76 g, 10 mmol) was slowly added. The reaction mixture was stirred at room temperature overnight. The reactants were concentrated under reduced pressure, and a saturated aqueous solution of NaHCO3 (15.0 mL) was added. The mixture was extracted with EtOAc (15 mL × 3), and the combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel eluting with a gradient of 10-50% EtOAc / heptane to afford tert-butyl (2S,5R)-5-(azidomethyl)-4-(3,6-dichloropyridazin-4-yl)-2-methylpiperazine-1-carboxylate (2.00 g, 70% yield) as a yellow oil. 15 H 22 LCMS calculated for Cl2N7O2 [M+H] +:m / z=402.1; found: 401.8.

[0531] Step 10: (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-carboxylic acid tert-butyl ester

[0532]

[0533] A solution of triphenylphosphine (5.50 g, 20.8 mmol) and (2S, 5R) -5- (azido-methyl) -4- (3,6-dichloropyridazin-4-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (7.00 g, 17.3 mmol) in THF (45.0 mL) was heated at 60 ° C for 3 hours. Water (4.50 mL) and NN-diisopropyl-ethylamine (9.00 mL, 51.9 mmol) were added, and the reaction mixture was stirred at 60 ° C overnight. The reactants were cooled to room temperature and concentrated under reduced pressure. The residual oil was diluted with water (40.0 mL) and extracted with EtOAc (50 mL × 3). The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel eluting with a gradient of 10-100% EtOAc / hexanes to afford 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 (1.50 g, 26% yield) as a yellow solid. 15 H 23 LCMS calculated for ClN5O2 [M+H] + :m / z=340.2; found: 340.0.

[0534] Step 11: (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)-dicarboxylic acid di-tert-butyl ester

[0535]

[0536] To a solution of (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- carboxylic acid tert-butyl ester (1.50 g, 4.41 mmol) in DCM (24.0 mL) was added triethylamine (1.23 mL, 8.83 mmol) and di-tert-butyl dicarbonate (1.35 g, 6.18 mmol) at 0 ° C. The reactant was stirred at room temperature overnight. The starting material was not completely consumed, and 4- dimethylaminopyridine (54.0 mg, 0.440 mmol) and additional di-tert-butyl dicarbonate (675 mg, 3.09 mmol) were added. The reactant was further stirred at room temperature for 3 hours. NH4Cl saturated aqueous solution (30.0 mL) was added, and the aqueous phase was extracted with DCM (30 mL × 3). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with a gradient of 10-50% EtOAc / hexanes to afford 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 (1.10 g, 57% yield) as a white solid. 20 H 31 LCMS calculated for ClN5O4 [M+H] + :m / z=440.2; found: 440.1.

[0537] Step 12: Di-tert-butyl (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)-dicarboxylate

[0538]

[0539] A mixture of (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)-dicarboxylic acid di-tert-butyl ester (420 mg, 0.950 mmol), (3,5-difluoro-2-hydroxyphenyl)-boronic acid (199 mg, 1.15 mmol), cesium carbonate (622 mg, 1.91 mmol) and XPhos Pd G2 (150 mg, 0.190 mmol) was degassed. After addition of 1,4-dioxane (4.00 mL) and water (0.500 mL), the reaction was stirred at 80° C. overnight. The mixture was diluted with DCM and washed with water. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel eluting with a gradient of 0-100% EtOAc / hexanes followed by 15% MeOH / DCM to afford di-tert-butyl (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)-dicarboxylate (380 mg, 75% yield). 26 H 34 LCMS calculated value of F2N5O5 [M+H] + :m / z=534.3; found: 534.2.

[0540] 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]pyridazin-2-yl)phenol

[0541]

[0542] A solution of di-tert-butyl (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)-dicarboxylate (200 mg, 0.370 mmol) in DCM (1.00 mL) was treated with 4N HCl solution in 1,4-dioxane (2.00 mL, 64.7 mmol) at room temperature for 1 hour. The mixture was concentrated under reduced pressure to afford 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 (120 mg, 79% yield) as an HCl salt. The material was used without further purification. 16 H18 LCMS calculated for F2N5O [M+H] + :m / z=334.2; found: 334.1.

[0543] 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]pyridazin-8-yl)methanone (Isomer 1)

[0544]

[0545] Step 1: (S)-1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid

[0546]

[0547] To a solution of (S)-piperazine-2-carboxylic acid; dihydrochloride (2.50 g, 12.3 mmol) in a mixture of water (4.92 mL) and 1,4-dioxane (19.7 mL) was added water (3.00 mL) containing sodium hydroxide (3.64 mL, 47.3 mmol) at 0°C, followed by di-tert-butyl dicarbonate (5.64 g, 25.9 mmol). The reaction was stirred at room temperature overnight. Imidazole (838 mg, 12.3 mmol) was added and the reaction was stirred at room temperature for 20 minutes. The reaction mixture was diluted with DCM, and the organics were washed with 1N aqueous HCl solution (4×25 mL) and saturated brine solution (1×25 mL). The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure to give crude (S)-1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (4.07 g) as a white solid. The material was used in the subsequent steps without further purification.

[0548] Step 2: (S)-piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl 2-methyl ester

[0549]

[0550] Iodomethane (0.283 mL, 4.55 mmol) was added 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) at 0 ° C. The reactants were 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 phase was extracted with EtOAc (3 × 25 mL), and the combined organics were washed with a saturated brine solution (1 × 25 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give crude (S)-piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl 2-methyl ester (2.14 g). The substance can be used in subsequent steps without further purification. C7H 13 LCMS calculated value of N2O4 [M+H-C9H 16 O2] + :m / z=189.1; found: 189.0.

[0551] Step 3: 2-Methylpiperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl 2-methyl ester (racemic mixture)

[0552]

[0553] LiHMDS (7.14 mL, 7.14 mmol) was added to a solution of (S)-piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl 2-methyl ester (2.14 g) in THF at -78 ° C. The reactants were stirred at -78 ° C for 2 hours. Iodomethane (741 μL, 11.9 mmol) was added, and the reactants were warmed to room temperature and stirred overnight. The reaction mixture was quenched with NH4Cl saturated aqueous solution (25 mL) and extracted with EtOAc (2 × 25 mL). The combined organics were washed with saturated brine solution (1 × 25 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel with a gradient elution of 0-100% EtOAc / hexane to give 2-methylpiperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl 2-methyl ester (2.10 g, 98% yield) as a clear oil. C8H 15 LCMS calculated value of N2O4 [M+H-C9H 16 O2] + :m / z=203.1; Found: 203.1.

[0554] 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)

[0555]

[0556] To a solution of 1,4-di-tert-butyl 2-methylpiperazine-1,2,4-tricarboxylate (2.50 g, 7.26 mmol) in DCM (43.6 mL) was carefully added DMF (436 μL) and oxalyl chloride (1.87 mL, 21.8 mmol). The mixture was stirred at room temperature for 30 minutes. The volatiles were removed under reduced pressure and DMF (13.1 mL), N,N-diisopropylethylamine (6.32 mL, 36.3 mmol) and 4-bromo-6-chloropyridazine-3-amine (3.03 g, 14.5 mmol) were added sequentially. The resulting mixture was stirred at 120 ° C overnight. The reaction mixture was diluted with EtOAc (100 mL) and washed with saturated brine solution (30 mL × 2). The combined organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with a gradient of 0-100% EtOAc / hexanes to afford 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 (929 mg, 36% yield) as a brown solid. 15 H 21 LCMS calculated value of ClN5O3 [M+H] + :m / z=354.1; Found: 354.1.

[0557] 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)

[0558]

[0559] A racemic mixture 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 (120 mg, 0.339 mmol) was subjected to chiral separation (LuxCellulose-2 column, 20 mL / min of 10:90 hexane / IPA:MeOH (1:1)) to give 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. -tert-Butyl 5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (55 mg, 46% yield, Peak A, Isomer 1) and 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 (45 mg, 38% yield, Peak B, Isomer 2). 15 H 21 LCMS calculated value of ClN5O3 [M+H] + :m / z=354.1; Found: 354.1.

[0560] Step 6: tert-Butyl 2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (isomer 1)

[0561]

[0562] A solution 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 (Peak A, Isomer 1) (55.0 mg, 0.155 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (complexed with dichloromethane (38.1 mg, 46.6 μL)), 3-fluoro-2-hydroxyphenylboronic acid (72.7 mg, 0.466 mmol) and potassium carbonate (107 mg, 0.777 mmol) in a mixture of 1,4-dioxane (1.41 mL) and water (0.141 mL) was bubbled with nitrogen for 5 minutes. The reactants were stirred at 90° C. for 2 hours. The reactants were cooled to room temperature and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with a gradient of 0-10% MeOH / DCM to afford tert-butyl 2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (Isomer 1) (47.5 mg, 71% yield). 21 H 25 LCMS calculated for FN5O4 [M+H] + :m / z=430.2; found: 430.1.

[0563] Step 7: tert-Butyl 2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (Isomer 1)

[0564]

[0565] At room temperature, a 1N solution of BH in THF (559 μL, 559 μmol) was added to a solution of tert-butyl 2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (isomer 1) (50.0 mg, 112 μmol) in THF (1.12 mL). The reactant was heated to 60 ° C and stirred for 24 hours. The reactant was cooled to room temperature and carefully diluted with MeOH (10 mL), and then heated at 80 ° C for 10 minutes. The reactant was cooled to room temperature, diluted with DCM, and the organic matter was washed with a saturated aqueous solution of NaHCO. The combined organic matter was dried over MgSO, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with a gradient of 0-20% MeOH / DCM to afford tert-butyl 2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (Isomer 1) (12.0 mg, 26% yield). 21 H 27 LCMS calculated for FN5O3 [M+H] + :m / z=416.2; Found: 416.2.

[0566] Step 8: 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 (Isomer 1)

[0567]

[0568] The title compound was prepared using a procedure analogous to that described for Intermediate 3, Step 13, substituting tert-butyl 2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino-[1′,2′:4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (Isomer 1) for di-tert-butyl (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)-dicarboxylate. 16 H 19 LCMS calculated value [M+H]+ for FN5O: m / z = 316.2; found: 316.1.

[0569] Step 9: tert-Butyl (3R,5S)-4-(chlorocarbonyl)-3,5-dimethylpiperazine-1-carboxylate

[0570]

[0571] A solution of triphosgene (2.24 g, 7.54 mmol) in DCM (15.0 mL) was carefully added dropwise to a solution of (3R, 5S)-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (2.15 g, 10.1 mmol) and pyridine (1.22 mL, 15.1 mmol) in DCM (25.0 mL) at 0 ° C. The reactant was warmed to room temperature and stirred for 2 hours. After completion, the reaction mixture was poured into 1N HCl aqueous solution (150 mL) while on ice and stirred for 15 minutes. The organic phase was separated and the aqueous phase was extracted with DCM (3 × 30 mL). The combined organics were washed with saturated brine solution (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel eluting with a gradient of 0-10% ethyl acetate in hexanes to afford tert-butyl (3R,5S)-4-(chlorocarbonyl)-3,5-dimethylpiperazine-1-carboxylate (1.66 g, 60% yield) as a white solid. 1 H NMR (300MHz, CDCl3) 4.40 (s, 2H), 4.15-3.77 (d, J = 18Hz, 2H), 3.05 (s, 2H), 1.52 (s, 9H), 1.40-1.27 (d, J = 12Hz, 6H).

[0572] 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)

[0573] 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 reactants were stirred at room temperature overnight. The reaction mixture was quenched with MeOH and a saturated aqueous solution of NaHCO3 was added. The aqueous phase was extracted with DCM, and 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 hour. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by prep-HPLC (Waters CSH-C18, 5 μM, 30×100 mm, 6.1-26.1% MeCN / water (containing 0.1% TFA) over 5 min) to give the TFA salt of the title compound as an oil (3.00 mg, 19% yield). 23 H 31 LCMS calculated value of FN7O2 [M+H]+: m / z=456.2; found value: 456.1.

[0574] 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)

[0575]

[0576] The title compound was prepared using procedures analogous to those described for Intermediate 4, Steps 1-10, substituting (2-chloro-6-hydroxyphenyl)boronic acid for 3-fluoro-2-hydroxyphenylboronic acid in Step 6, and substituting (3R,5R)-tert-butyl 4-(chlorocarbonyl)-3,5-dimethylpiperazine-1-carboxylate for (3R,5S)-tert-butyl 3,5-dimethylpiperazine-1-carboxylate in Step 9. 23 H 31 LCMS calculated value of ClN7O2 [M+H]+: m / z=472.2; found: 472.0.

[0577] Intermediate 6-19:

[0578] The intermediates shown in Table 1 below were prepared by procedures analogous to those described for the preparation of Intermediate 4 using appropriate starting materials.

[0579] Table 1. Intermediates 6-19

[0580]

[0581]

[0582]

[0583] Intermediate 20: 3-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0584]

[0585] Step 1: Methyl 2-cyano-5-(4-(hydroxymethyl)piperidin-1-yl)benzoate

[0586]

[0587] To a solution of methyl 2-cyano-5-fluorobenzoate (2.00 g, 11.2 mmol) and 4-piperidinemethanol (1.67 g, 14.5 mmol) in dimethyl sulfoxide (22.3 mL) was added N, N-diisopropylethylamine (5.83 mL, 33.5 mmol). The reaction mixture was heated to 110 ° C and stirred for 1.5 hours. The product mixture was diluted with EtOAc (100 mL) and transferred to a separatory funnel. The diluted reaction mixture was washed with a saturated aqueous solution of sodium chloride (50 mL × 2). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel with a gradient elution of 0-100% EtOAc / hexane to give methyl 2-cyano-5-(4-(hydroxymethyl)piperidin-1-yl)benzoate (3.02 g, 98% yield) as a yellow oil. 15 H 18 LCMS calculated for N2O3 [M+H] + :m / z=275.1; Found: 275.1.

[0588] Step 2: Methyl 2-formyl-5-(4-(hydroxymethyl)piperidin-1-yl)benzoate

[0589]

[0590] To a solution of 2-cyano-5-(4-(hydroxymethyl)piperidin-1-yl)benzoic acid methyl ester (3.00 g, 10.9 mmol), sodium hypophosphite monohydrate (11.7 g, 111 mmol) and acetic acid (12.7 mL, 222 mmol) in pyridine (26.3 mL) was added a slurry of Raney nickel (1.97 g, 33.6 mmol) in water (28.0 mL). The reaction mixture was heated to 70 ° C and stirred for 8 hours. The product mixture was filtered through diatomaceous earth, and the diatomaceous earth was washed with EtOAc (50 mL × 2). The filtrate was transferred to a separatory funnel and washed with water (150 mL). The aqueous layer was extracted with EtOAc (75 mL × 2). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel eluting with a gradient of 0-100% EtOAc / hexanes to afford methyl 2-formyl-5-(4-(hydroxymethyl)piperidin-1-yl)benzoate (2.31 g, 76.0%) as a yellow oil. 15 H 20 LCMS calculated value of NO4 [M+H] + :m / z=278.1; Found: 278.1.

[0591] Step 3: 3-(6-(4-(Hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0592] To a stirred solution of 2-formyl-5-(4-(hydroxymethyl)piperidin-1-yl)benzoic acid methyl ester (2.40g, 8.65mmol) in DCM (48.8mL) and DMF (48.8mL) was added 3-aminopiperidine-2,6-dione hydrochloride (1.85g, 11.3mmol) followed by N,N-diisopropylethylamine (3.77mL, 21.6mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled to 0°C and acetic acid (5.94mL, 104mmol) was added followed by sodium triacetoxyborohydride (5.50g, 26.0mmol). The reaction mixture was slowly warmed to room temperature and stirred for an additional 3 hours. The reaction mixture was diluted with water (10mL) and the solution was basified with a saturated aqueous solution of NaHCO until no further evolution of gas was observed. The alkalized product mixture was filtered and the solid was washed with water (10mL×2). The solid was collected and dried in vacuo to give 3-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.95 g, 63%) as an off-white solid. 19 H 23 LCMS calculated for N3O4 [M+H] + :m / z=358.2; found: 358.1.

[0593] Intermediates 21-26:

[0594] The intermediates shown in Table 2 below were prepared by procedures analogous to those described for the preparation of intermediate 20 using appropriate starting materials.

[0595] Table 2. Intermediates 21-26

[0596]

[0597] Intermediate 27: (S)-3-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0598]

[0599] Step 1: (S)-tert-Butyl 5-amino-4-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate

[0600]

[0601] 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) were loaded into a solution of 2- formyl -5- [4- (hydroxymethyl) piperidin-1-yl] methyl benzoate (3.0 g, 10.82 mmol) in DCM (45 mL). The reaction mixture was stirred at RT for 30 minutes and then cooled to 5 ° C. Sodium triacetoxyborohydride (0.840 g, 3.97 mmol) was loaded in batches at 5 ° C. and then stirred at room temperature overnight. After dilution with DCM (45 mL), the reactant was quenched with NaHCO3 saturated aqueous solution until bubbles were no longer observed while forming a white precipitate. The precipitate was filtered and washed with water and DCM. The solid was collected and dried under vacuum to give a white solid (4.1 g, 88% yield, 98.4% ee). 23 H 34 LCMS calculated value of N3O5 [M+H] + :m / z=432.1; Found:432.1

[0602] Step 2: (S)-tert-Butyl 4-(6-(4-(acetoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate

[0603]

[0604] To a stirred solution of (S)-tert-butyl 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 charged N,N-diisopropylethylamine (1.33 mL, 7.65 mmol) followed by acetyl chloride (0.74 mL, 10.4 mmol). The reaction was stirred at RT for 2 hours. The reaction was quenched with saturated NaHCO, extracted with DCM, dried over NaSO, and purified by flash chromatography with 5% MeOH / DCM to give a light yellow solid (3.1 g, 94%). 25 H 36 LCMS calculated value of N3O6 [M+H] + :m / z=474.1; Found: 474.1.

[0605] Step 3: (S)-3-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0606] To a stirred solution of (S)-4-(6-(4-(acetoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoic acid tert-butyl ester (1.15 g, 2.43 mmol) in MeCN (12.0 mL) was charged benzenesulfonic acid (768.0 mg, 4.86 mmol). The reaction mixture was heated to 85 ° C. After 2 hours, the reactant was cooled to RT and charged with water (12 mL), then stirred at 75 ° C for 4 hours until LCMS showed complete conversion. The reaction mixture was evaporated to remove volatiles, and the residue was cooled to 5 ° C and slowly charged with NaHCO3 aqueous solution until pH = 6-7, during which time a white precipitate was formed. Filtered and washed with water. The solid was collected and dried in vacuo to give an off-white solid (730 mg, 84% yield, 98.2% ee). 19 H 24 LCMS calculated for N3O4 [M+H] + :m / z=358.2; Found:358.1

[0607] Intermediate 28

[0608] The intermediates shown in Table 3 below were prepared by the method used to prepare Intermediate-27 using appropriate starting materials.

[0609] Table 3. Intermediate 28

[0610]

[0611] Intermediate 29: 3-(5-((R)-2-(hydroxymethyl)morpholino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0612]

[0613] Step 1: (R)-methyl 2-cyano-4-(2-(hydroxymethyl)morpholino)benzoate

[0614]

[0615] To a stirred solution of (R)-morpholin-2-ylmethanol (255mg, 2.18mmol), 2-cyano-4-fluorobenzoic acid methyl ester (300mg, 1.67mmol) in NMP (6.70mL) was added N, N-diisopropyl-ethylamine (0.88mL, 5.02mmol). The reactant was heated to 120 ° C and stirred for 1.5 hours. The reaction mixture was cooled to room temperature and diluted with DCM and saturated saline solution. The aqueous layer was extracted twice with DCM. The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel with a gradient elution of 0-100% EtOAc / hexane to obtain (R)-2-cyano-4-(2-(hydroxymethyl)morpholino)benzoic acid methyl ester (401mg, 87% yield) as a yellow oil. 14 H 17 LCMS m / z calculated for N2O4 [M+H] + :m / z=277.1; found: 277.0.

[0616] Step 2: (R)-methyl 2-formyl-4-(2-(hydroxymethyl)morpholino)benzoate

[0617]

[0618] By (R) -2- cyano -4- (2- (hydroxymethyl) morpholino) methyl benzoate (401mg, 1.45mmol), pyridine (3.50mL, 43.2mmol), acetic acid (1.70mL, 29.4mmol) and sodium hypophosphite monohydrate (1.55g, 14.67mmol) slurry treatment with Raney nickel (262mg, 4.46mmol) in water (3.70mL). Reactant is heated to 70 DEG C and stirred for 8 hours, while being monitored by LCMS. Reactant mixture is filtered through diatomaceous earth, and diatomaceous earth is washed with EtOAc and water. With EtOAc aqueous layer extracted, and through NaSOThe organic matter that merges is dried, filtered and concentrated under reduced pressure. With the gradient elution of 0-100% EtOAc / hexane, crude material is purified by flash column chromatography on silica gel. The product was obtained as a yellow oil to give (R)-methyl 2-formyl-4-(2-(hydroxymethyl)morpholino)benzoate (308 mg, 76% yield). 14 H 18 LCMS calculated value of NO5 [M+H] + :m / z=280.1; found: 280.0.

[0619] Step 3: 3-(5-((R)-2-(hydroxymethyl)morpholino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0620] N, N- diisopropylethylamine (0.58mL, 3.31mmol) is added to (R) -2- formyl -4- (2- (hydroxymethyl) morpholino) benzoic acid methyl ester (308mg, 1.10mmol) and 3- amino - piperidine -2,6- dione, HCl (272mg, 1.65mmol) in DCM (5.50mL). The reactant is stirred at room temperature overnight. The reactant is cooled to 0 DEG C and acetic acid (0.760mL, 13.2mmol) and sodium triacetoxyborohydride (701mg, 3.31mmol) are added. The reactant is stirred at 0 DEG C until completion. NaHCO saturated aqueous solution is added and the crude reaction mixture is concentrated under reduced pressure. The crude material was dissolved in DMSO, and the filtrate was purified by prep-HPLC (Waters CSH-C18 column, 7.2-27.2% MeCN / water with 0.1% TFA over 5 min) to afford 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. 18 H 22 LCMS m / z calculated for N3O5 [M+H] + :m / z=360.2; found: 360.1.

[0621] Intermediate 30: 2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione

[0622]

[0623] Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione

[0624] N, N-diisopropylethylamine (0.380mL, 2.17mmol) is added to a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (200mg, 0.720mmol) and 4-piperidine-methanol (208mg, 1.81mmol) in NMP (7.24mL). The reactants are heated to 100 ° C and monitored by LCMS until completion. The reactants are cooled to room temperature, and the solution is filtered and purified by prep-HPLC (Waters CSH-C18 column, 18.3-38.3% MeCN / water (containing 0.1% TFA), after 5min) to give 2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione TFA salt (185mg, 53% yield) as a yellow solid. 19 H 22 LCMS m / z calculated for N3O5 [M+H] + :m / z=372.2; found: 372.0.

[0625] 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

[0626]

[0627] Step 1. 2-(Difluoromethyl)piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl 2-methyl ester

[0628]

[0629] LiHMDS (1M in THF, 31.9mL, 31.9mmol) was added to a solution of (S)-piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl 2-methyl ester (5.5g, 16mmol) in THF (80mL) at -78°C. The reactants were stirred at -78°C for 1 hour. Difluoromethyl trifluoromethanesulfonate (6.07mL, 47.9mmol) was added to the reaction mixture, and the reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated aqueous NH4Cl solution (200mL) and extracted with EtOAc (2×200mL). The combined organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel with a gradient of 0-30% EtOAc / hexanes to afford 2-methyl 1,4-di-tert-butyl 2-(difluoromethyl)piperazine-1,2,4-tricarboxylate (6.0 g, 95%) as an orange oil. 13 LCMS calculated values ​​of F2N2O4 [M+H-C9H 16 O2] + :m / z=239.1; Found:239.0

[0630] Step 2. 1,4-Bis(tert-butoxycarbonyl)-2-(difluoromethyl)piperazine-2-carboxylic acid

[0631]

[0632] Lithium hydroxide (3.3 g, 0.14 mol) was added to a solution of 2-(difluoromethyl)piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl 2-methyl ester (5.5 g, 13.9 mmol) in THF (100 mL), methanol (40 mL) and water (40 mL) at room temperature. The reaction mixture was heated to 60 ° C and stirred overnight. The reaction mixture was quenched with 1M HCl solution (200 mL). The product mixture was transferred to a separatory funnel and extracted with DCM (2×200 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was used in the next step without purification. 1,4-bis(tert-butoxycarbonyl)-2-(difluoromethyl)piperazine-2-carboxylic acid (5.3 g, 100%) was obtained as a white foam. C7H 11 LCMS calculated values ​​of F2N2O4 [M+H-C9H 16 O2] + :m / z=225.1; Found:225.0

[0633] Step 3. Di-tert-butyl 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)-dicarboxylate

[0634]

[0635] Oxalyl chloride (1.55mL, 18.1mmol) was added dropwise to a stirred solution of DMF (1.4mL, 18.1mmol) and DCM (35mL) at 0°C. The reaction mixture was stirred for 10 minutes at 0°C. Subsequently, a solution of 1,4-bis(tert-butoxycarbonyl)-2-(difluoromethyl)piperazine-2-carboxylic acid (5.3g, 13.9mmol) and pyridine (1.69mL, 20.9mmol) in DCM (10mL) was added to the reaction mixture at 0°C. After addition, the reaction mixture was stirred at 0°C for 30 minutes. The reaction mixture was then transferred to a separating funnel and washed with water (2 × 30mL) and a saturated aqueous solution of sodium chloride (30mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was dissolved in DMF (28 mL), and N, N-diisopropylethylamine (7.28 mL, 41.8 mmol) and 4-bromo-6-chloropyridazine-3-amine (2.76 g, 13.2 mmol) were added sequentially. The obtained mixture was stirred at 120 ° C overnight. The product mixture was diluted with EtOAc (200 mL) and washed with a saturated aqueous solution of sodium chloride (2 × 200 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography using a gradient of 0-100% EtOAc / hexane to obtain 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-carboxylic acid tert-butyl ester in the form of a mixture with 4-bromo-6-chloropyridazine-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 flash column chromatography on silica gel with a gradient of 0-100% EtOAc / hexane to give di-tert-butyl 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)-dicarboxylate (523 mg, 8%) as a light yellow foamy solid. 20 H 26 LCMS calculated value of ClF2N5O5 [M+H] + :m / z=490.2; Found:489.9

[0636] Step 4. Chiral separation of di-tert-butyl 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)-dicarboxylate

[0637]

[0638] A racemic mixture of di-tert-butyl 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)-dicarboxylate (523 mg) was purified via chiral separation (Lux Cellulose-1, 20 mL / min of 80:10:10 hexanes / IPA / MeOH) to afford (S)-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)-dicarboxylate. ,9,10-tetrahydro-5H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylic acid di-tert-butyl ester (185 mg, peak A, 35%) and (R)-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 ester (196 mg, peak B, 37%). 20 H 26 LCMS calculated value of ClF2N5O5 [M+H] + :m / z=490.2; Found:489.9

[0639] Step 5. (S)-tert-Butyl 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-carboxylate

[0640]

[0641] Into a 20mL scintillation vial was charged (S) -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- tert-butyl carboxylate (326mg, 0.66mmol), cesium carbonate (650mg, 2.0mmol), XPhos Pd G2 (52.4mg, 0.066mmol) and 3- fluoro -2- hydroxyphenyl boronic acid (239mg, 1.5mmol). The mixture was dissolved in 1,4- dioxane (4mL) and water (0.5mL). The reaction mixture was bubbled with N2 gas for 2 minutes, sealed and heated to 80°C. The reaction mixture was stirred for 2 hours at 80°C. The product mixture was diluted with EtOAc (50mL) and washed with water (100mL). The aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel with a gradient of 0-100% EtOAc / hexane to afford (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 ester (205 mg, 66%) as a pale oil. 21 H 22 LCMS calculated for F3N5O4 [M+H] + :m / z=466.2; Found:466.0

[0642] Step 6. (R)-tert-Butyl 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-carboxylate

[0643]

[0644] Borane tetrahydrofuran complex (1M, 7.4mL, 7.4mmol) was added to a solution of (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 ester (570mg, 1.22mmol) in THF (8.5mL) at room temperature. The reaction mixture was heated to 60°C for 2 hours. The reaction mixture was cooled to 0°C and slowly quenched with MeOH (3mL). The reaction mixture was diluted with EtOAc (100mL). The diluted reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate (2×100mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was dissolved in THF (8.5mL) and MeOH (3.7mL). Acetic acid (2.1 mL, 36.7 mmol) and sodium cyanoborohydride (770 mg, 12.2 mmol) were added to the reaction mixture in sequence at room temperature. The reaction mixture was refluxed at 80 ° C for 16 hours. The product mixture was cooled to room temperature and diluted with EtOAc (100 mL). The diluted reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate (2 × 100 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 with a gradient of 0-15% MeOH / DCM 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]pyridazine-8-carboxylic acid tert-butyl ester (455 mg, 82%) as a dark oil. 21 H 25 LCMS calculated for F3N5O3 [M+H] + :m / z=452.2; Found:452.1

[0645] 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

[0646]

[0647] Hydrochloric acid (4M in 1,4-dioxane, 3.8 mL, 15.2 mmol) was added to a solution of (R)-tert-butyl 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-carboxylate (455 mg, 1.0 mmol) in DCM (10 mL) at room temperature. The reaction was stirred overnight. The product mixture was concentrated under reduced pressure to give the HCl salt 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 as a brown solid (427 mg, 100%). 16 H 17 LCMS calculated for F3N5O [M+H] + :m / z=352.1; Found:352.1

[0648] Step 8. tert-Butyl 4-(chlorocarbonyl)-3,3-dimethylpiperazine-1-carboxylate

[0649]

[0650] Triphosgene (415 mg, 1.4 mmol) was added portionwise to a stirred solution of tert-butyl 3,3-dimethylpiperazine-1-carboxylate (500 mg, 2.33 mmol) and pyridine (570 μL, 7.0 mmol) in DCM (20 mL) at 0 ° C. The reactants were warmed to room temperature and stirred for 2 hours. The product mixture was washed with 1M HCl aqueous solution (50 mL). The aqueous layer was extracted with DCM (2 × 50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was used without further purification. tert-Butyl 4-(chlorocarbonyl)-3,3-dimethylpiperazine-1-carboxylate (650 mg, 100%) was obtained as a yellow oil.

[0651] Step 9. (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazine-1-carboxylate

[0652]

[0653] N, N-diisopropylethylamine (701 μL, 4.0 mmol) and 4-(dimethylamino)pyridine (36.9 mg, 0.30 mmol) were added sequentially 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 a saturated aqueous solution of sodium bicarbonate (100 mL). The aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel with a gradient of 0-15% MeOH / DCM to give (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 ester (502 mg, 84.3%) as a yellow oil. C 28 H 37 LCMS calculated for F3N7O4 [M+H] + :m / z=592.3; found: 592.2.

[0654] 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

[0655] Trifluoroacetic acid (1.54 mL, 20.1 mmol) was added to a stirred solution of (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]pyridazine-8-carbonyl)-3,3-dimethylpiperazine-1-carboxylate (502 mg, 0.85 mmol) in DCM (10 mL) at room temperature. The reaction was stirred at room temperature for 1 hour. The product mixture was concentrated under reduced pressure 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]pyridazin-8-yl)(2,2-dimethylpiperazin-1-yl)methanone trifluoroacetic acid salt (610 mg, 100%) as an oil. 23 H 29 LCMS calculated for F3N7O2 [M+H] + :m / z=492.2; found: 492.0.

[0656] 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

[0657]

[0658] 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

[0659]

[0660] Hydrochloric acid (4M in dioxane, 0.21 mL, 0.86 mmol) was added to a stirred solution of (S)-tert-butyl 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-carboxylate (40 mg, 0.086 mmol) in DCM (2 mL). The reaction mixture was stirred overnight. The product mixture was concentrated under reduced pressure to afford the HCl salt of (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 (37 mg, 99%). 16 H 14 LCMS calculated for F3N5O2 [M+H] + :m / z=366.1; Found:366.0

[0661] Step 2. 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

[0662]

[0663] N,N-diisopropylethylamine (30 μL, 0.17 mmol) and 4-(dimethylamino)pyridine (1.6 mg, 0.013 mmol) were 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 (19.2 mg, 0.043 mmol) in dimethylacetamide (1 mL) at room temperature. The reaction mixture was stirred for 15 minutes. A solution of tert-butyl (3R,5S)-4-(chlorocarbonyl)-3,5-dimethylpiperazine-1-carboxylate (18 mg, 0.065 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 (25 mL) and washed with a saturated aqueous solution of sodium bicarbonate (25 mL). The aqueous layer was extracted with EtOAc (2×25 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel with a gradient of 0-10% MeOH / DCM to give (3R, 5S)-4-((S)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxy-phenyl)-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 ester (37 mg, 71%) as a yellow oil. C 28 H 34 LCMS calculated for F3N7O5 [M+H] + :m / z=606.3; Found:606.3

[0664] 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

[0665] Borane tetrahydrofuran complex (1M in THF, 0.53mL, 0.53mmol) was added to a stirred solution of (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 ester (80mg, 0.132mmol) in THF (1mL) 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 (2mL). The quenched product mixture was heated to 80°C and stirred for 30 minutes. The product mixture was concentrated under reduced pressure. The resulting residue was dissolved in DCM (2mL). Trifluoroacetic acid (300 μL, 3.96 mmol) was added to the dissolved residue and stirred at room temperature for 1 hour. The product mixture was concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile and purified by prep-HPLC (Waters CSH-Flouro-Phenyl, 5 μM, 30 × 100 mm, 5-25% MeCN / water (containing 0.1% TFA), over 5 min) 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] pyridazine -8- base) ((2R, 6S) -2,6- dimethylpiperazin-1-yl)methanone (16 mg, 20%) in the form of a TFA salt. 23 H 28 LCMS calculated for F3N7O2 [M+H] + :m / z=492.2; Found:492.1

[0666] Intermediates 33-36

[0667] The intermediates shown in Table 4 below were prepared by procedures analogous to those described for the preparation of intermediate 31 using appropriate starting materials.

[0668] Table 4. Intermediates 33-36

[0669]

[0670]

[0671] Intermediate 37: (S)-1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-4-carboxaldehyde

[0672]

[0673] Step 1. Methyl 2-cyano-5-[4-(hydroxymethyl)piperidin-1-yl]benzoate

[0674]

[0675] To a solution of methyl 2-cyano-5-fluorobenzoate (5.0 g, 27.9 mmol) and 4-piperidine-methanol (9.64 g, 83.7 mmol) in NMP (20 mL) was added N, N-diisopropylethylamine (7.29 mL, 41.9 mmol), and the reactants were heated at 120 ° C for 4 h. DIPEA was removed using rotary evaporation. The solution was further diluted with ethyl acetate and washed with H2O. The organic layer was collected and dried over Na2SO4, filtered and concentrated. The crude product was purified by FCC (0% to 40% EA / heptane) to give the title compound (5.1 g, 18.6 mmol, 67% yield) as a light yellow solid. LCMS: (M+H) + =275.1.

[0676] Step 2. Methyl 2-cyano-5-(4-formylpiperidin-1-yl)benzoate

[0677]

[0678] To a solution of 2-cyano-5-[4-(hydroxymethyl)piperidin-1-yl]benzoic acid methyl ester (2.5g, 9.1mmol) in DCM (30mL) was added Dess-Martin periodinane (5.8g, 13.7mmol) at 0°C. The reactant was stirred at room temperature for 15min, and TLC monitoring showed that the starting material was completely consumed (eluent: 100% EA). The reaction mixture was diluted with DCM and quenched by saturated NaHCO3 until bubbling stopped. The aqueous phase was extracted with DCM, and the organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by FCC (10% to 85% EA / heptane) to obtain the title compound, which was then carried out to the next step without further purification. 1 H NMR (300MHz, CDCl3) δ9.71 (s, 1H), 7.64-7.46 (m, 2H), 6.99 (dt, J = 10.4, 5.2Hz, 1H), 3.98 (dt, J =13.1,4.1Hz,2H),3.22-3.05(m,2H),2.65-2.47(m,1H),2.12-1.99(m,2H),1.85-1.67(m,2H).

[0679] Step 3. Methyl 2-cyano-5-[4-(dimethoxymethyl)piperidin-1-yl]benzoate

[0680]

[0681] To a solution of methyl 2-cyano-5-(4-formylpiperidin-1-yl)benzoate (2.1 g, 7.71 mmol) in methanol (30 mL) was added trimethyl orthoformate (2.54 mL, 23.1 mmol) at 0°C. The reaction was stirred at room temperature for 7 h. The reaction was quenched by the addition of TEA (0.2 equiv), the solvent was concentrated under reduced pressure, and the crude material was dissolved in ethyl acetate. This solution was washed with water (30 mL x 2), the organic phase was collected, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by FCC (0% to 45% EA / heptane) to give the title compound (1.26 g, 3.9 mmol, 52% yield). 1 H NMR (300MHz, CDCl3) δ7.62-7.47(m,2H),6.97(dd,J=8.8,2.8Hz,1H),4.06(d,J=6.5Hz,1H),3.98(s,3H),3.93(d,J=1 2.9Hz,2H),3.43-3.30(m,6H),2.89(td,J=12.9,2.4Hz,2H),1.95-1.79(m,3H),1.39(ddd,J=16.0,13.5,3.6Hz,2H).

[0682] Step 4. Methyl 5-[4-(dimethoxymethyl)piperidin-1-yl]-2-formylbenzoate

[0683]

[0684] To a solution of 2-cyano-5-[4-(dimethoxymethyl)piperidin-1-yl]benzoic acid methyl ester (1.2g, 3.77mmol) in pyridine (2.44mL, 30.2mmol) and acetic acid (2.16mL, 37.7mmol) was added sodium phosphinate hydrate (0.8g, 7.54mmol) and water (5mL). A slurry of Raney nickel in water (663mg, 11.3mmol) was added to the stirred solution in portions to avoid emulsion formation. The reactants were heated to 75°C overnight. Heating was stopped, and the reactants were cooled, diluted with MeOH, filtered through diatomaceous earth, and washed with MeOH. The filtrate was concentrated to remove pyridine and methanol. The residue was dissolved in ethyl acetate and washed with water. The organic phase was dried over Na2SO4, filtered and concentrated. The product was purified by FCC (0% to 35% EA / heptane) to obtain the title compound (742mg, 2.31mmol, 61% yield).

[0685] Step 5: (S)-methyl 5-amino-4-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate

[0686]

[0687] To a solution of 5-[4-(dimethoxymethyl)piperidin-1-yl]-2-formylbenzoic acid methyl ester (450.0 mg, 1.4 mmol) in DCM (2 mL) and DMF (2 mL) was added N, N-diisopropylethylamine (0.61 mL, 3.5 mmol) and (S)-4,5-diamino-5-oxopentanoic acid methyl esters (269 mg, 1.68 mmol). The reactant was stirred at rt for 1 h and acetic acid (0.8 mL, 14. mmol) was added to this solution. The reactant was further stirred for another hour, and sodium triacetoxyborohydride (890 mg, 4.2 mmol) was added, and the reactant was stirred during the weekend. The reaction was stopped, diluted with DCM (50 mL), and quenched dropwise by saturated NaHCO solution until pH was maintained at 8-9. The organic phase was collected, dried over NaSO, filtered and concentrated. The residue was purified by FCC (0% to 100% EA / heptane) to afford the title compound (400 mg, 0.93 mmol, 66% yield).

[0688] Step 6: (S)-3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0689]

[0690] A 1.0 M solution of potassium tert-butoxide (8.30 mL, 8.30 mmol) in THF was added to a solution of (S)-methyl 5-amino-4-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (3.00 g, 6.92 mmol) in THF (80.0 mL) at -78°C and the reaction was stirred for 3 hours. The reaction was warmed to 0°C and the pH was carefully adjusted to approximately 3 using 1N aqueous HCl. To this solution was carefully added dropwise a saturated aqueous solution of NaHCO₃ to adjust the pH to approximately 6. DCM was added and the phases separated. The combined organics were washed with water, dried over MgSO₄, filtered and concentrated under reduced pressure. The crude material was triturated with DCM (5.00 mL) followed by MTBE (20.0 mL) after which a white precipitate settled out. The solid was filtered and dried by vacuum filtration to afford 3-(6-(4-(dimethoxymethyl)piperidin-l-yl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione (1.89 g, 68% yield).1 HNMR (300MHz, DMSO) δ10.97 (s, 1H), 7.41 (d, J = 8.4Hz, 1H), 7.25 (dd, J = 8.5, 2.3Hz, 1H), 7.14 (d, J = 2. 2Hz, 1H), 5.10 (dd, J = 13.3, 5.1Hz, 1H), 4.33 (d, J = 16.8Hz, 1H), 4.19 (d, J = 16.7Hz, 1H), 4.08 (d, J = 6. 6Hz,1H),3.77(d,J=12.3Hz,2H),3.27(s,6H),2.98-2.82(m,1H),2.65(dd,J=29.4,15.4Hz,3H),2.3 8(qd,J=13.3,4.4Hz,1H),2.04-1.92(m,1H),1.72(d,J=10.8Hz,3H),1.34(dt,J=21.6,10.9Hz,2H).

[0691] Step 7: (S)-1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-4-carbaldehyde

[0692] 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 give the title compound as a TFA salt (440 mg, quantitative yield). 19 H 22 LCMS calculated for N3O4 (M+H) + m / z=356.2; found: 356.2.

[0693] Intermediate 38: 1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-4-carboxaldehyde

[0694]

[0695] Trifluoroacetic acid (2.38 mL, 31.1 mmol) was added to a stirred solution of 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (500 mg, 1.25 mmol) in DCM (9.3 mL) and acetone (3.1 mL) at room temperature. The reaction mixture was stirred at room temperature for 48 hours. The product mixture was concentrated. The resulting residue was dissolved in DCM (100 mL) and transferred to a separatory funnel containing a saturated aqueous solution of sodium carbonate (50 mL) and a saturated aqueous solution of sodium bicarbonate (50 mL). The aqueous layer was extracted with DCM (3×100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-4-carbaldehyde (440 mg, 99%) as a white solid. 19 H 22 LCMS calculated for N3O4 [M+H] + :m / z=356.2; found: 356.1.

[0696] Intermediate 39: (S)-3-(1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

[0697]

[0698] This compound was prepared by a procedure analogous to that described for Intermediate 37, utilizing tert-butyl piperazine-1-carboxylate in place of 4-piperidinemethanol in Step 1. 17 H 21 LCMS calculated value of N4O3 (M+2H-Boc) + m / z = 329.2; found: 329.1.

[0699] 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)

[0700]

[0701] Step 1. 2-Methyl 1,4-di-tert-butyl 2-ethylpiperazine-1,2,4-tricarboxylate

[0702]

[0703] LiHMDS (1M in THF, 5.3mL, 5.3mmol) was added to a solution of (S)-piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl 2-methyl ester (1.3g, 3.77mmol) in THF (19mL) at -78°C. The reaction mixture was stirred at -78°C for 2 hours. Iodoethane (0.91mL, 11.3mmol) was added to the reaction mixture at -78°C. The reaction mixture was stirred overnight and allowed to slowly warm to room temperature. The product mixture was quenched with a saturated aqueous solution of ammonium chloride (30mL). The quenched product mixture was diluted with EtOAc (50mL). The organic layer was washed with water (30mL) and a saturated solution of sodium chloride (30mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel with a gradient of 0-60% EtOAc / hexanes to afford 2-methyl 1,4-di-tert-butyl 2-ethylpiperazine-1,2,4-tricarboxylate (1.2 g, 85%) as a clear oil. 17 LCMS calculated value of N2O4 [M+2H-C9H 16 O2] + :m / z=217.1; Found: 217.1.

[0704] Step 2. 1,4-Bis(tert-butoxycarbonyl)-2-ethylpiperazine-2-carboxylic acid

[0705]

[0706] 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 1M aqueous HCl (70 mL). The diluted reaction mixture was extracted with DCM (2 × 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. CH 15 LCMS calculated value of N2O4 [M+2H-C9H 16 O2] + :m / z=203.1; Found: 203.1.

[0707] Step 3. 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

[0708]

[0709] Oxalyl chloride (0.76 mL, 8.86 mmol) was added dropwise to a stirred solution of 1,4-bis(tert-butoxycarbonyl)-2-ethylpiperazine-2-carboxylic acid (1.27 g, 3.54 mmol) and dimethylformamide (270 μL, 3.5 mmol) in DCM (27 mL) at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 40 minutes. The reaction mixture was concentrated under reduced pressure and then redissolved with DMF (8.1 mL). N, N-diisopropylethylamine (3.1 mL, 17.7 mmol) and 4-bromo-6-chloropyridazine-3-amine (1.48 g, 7.09 mmol) were added sequentially to the stirred reaction mixture at room temperature. The reaction mixture was heated to 120 ° C and stirred for 18 hours. The product mixture was diluted with EtOAc (80 mL) and washed with a saturated aqueous solution of sodium chloride (80 mL). The aqueous layer was extracted with EtOAc (2 × 80 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel using a gradient of 0-100% EtOAc / hexane to afford 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 (401 mg, 31%) as a white solid. 16 H 23 LCMS calculated value of ClN5O3 [M+H] + :m / z=368.2; found: 368.1.

[0710] Step 4. 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

[0711]

[0712] Di-tert-butyl dicarbonate (470 μL, 2.07 mmol) and 4-(dimethylamino)pyridine (38 mg, 0.31 mmol) were added sequentially to a stirred solution 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 (380 mg, 1.03 mmol) in THF (10 mL) at room temperature. The reaction mixture was stirred for 5 hours. The product mixture was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel with a gradient of 0-100% EtOAc / hexanes to afford 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 (310 mg, 64%) as a tan foamy solid. 21 H 31 LCMS calculated value of ClN5O5 [M+H] + :m / z=468.2; found: 468.0.

[0713] Step 5. Chiral separation 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

[0714]

[0715] A racemic mixture 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 was separated by chiral separation (310 mg) (Lux The mixture was purified by Cellulose-4, 25 mL / min of 55:22.5:22.5 hexanes / IPA / MeOH to give 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 (118 mg, peak A, isomer 1, 38%) and 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 (137 mg, peak B, isomer 2, 44%). 21 H 31 LCMS calculated value of ClN5O5 [M+H] + :m / z=468.2; found: 468.1.

[0716] Step 6. 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)

[0717]

[0718] Into a 20mL scintillation vial was charged 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)-dicarboxylic acid di-tert-butyl ester (isomer 1) (227mg, 0.49mmol), cesium carbonate (474mg, 1.46mmol), XPhos Pd G2 (57.3mg, 0.073mmol) and 3-fluoro-2-hydroxyphenylboronic acid (151mg, 0.97mmol). The mixture was dissolved in 1,4-dioxane (4mL) and water (0.5mL). The reaction mixture was bubbled with N2 gas for 2 minutes, sealed and heated to 80°C. The reaction mixture was stirred at 80°C for 2 hours. The product mixture was diluted with EtOAc (50mL) and washed with water (100mL). 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 flash column chromatography on silica gel using a gradient of 0-30% acetone / hexane to afford 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) (130 mg, 60%).

[0719] Step 7. 6a-Ethyl-2-(3-fluoro-2-hydroxyphenyl)-7,8,9,10-tetrahydro-5H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-6(6aH)-one (Isomer 1)

[0720]

[0721] Hydrochloric acid (4M 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 give 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]pyridazine-6(6aH)-one (Isomer 1) (120 mg, 100%). 17 H 19 LCMS calculated for FN5O2 [M+H] + :m / z=344.2; found: 344.1.

[0722] Step 8. 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-dimethyl-piperazine-1-carboxylate (Isomer 1)

[0723]

[0724] N, N-diisopropylethylamine (220 μL, 1.26 mmol) and 4-(dimethylamino)pyridine (11.6 mg, 0.095 mmol) were added to a stirred solution of 6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-7,8,9,10-tetrahydro-5H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazine-6(6aH)-one (120 mg, 0.316 mmol) in dimethylacetamide (3 mL) at room temperature. The reaction mixture was stirred for 15 minutes. A solution of tert-butyl 4-(chlorocarbonyl)-3,3-dimethylpiperazine-1-carboxylate (131 mg, 0.474 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 (50 mL) and washed with a saturated aqueous solution of sodium bicarbonate (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel with a gradient of 0-100% EtOAc / hexane to give 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 (170 mg, 92%) as a yellow oil. 29 H 39 LCMS calculated value of FN7O5 [M+H] + :m / z=584.3; found: 584.2.

[0725] 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)

[0726]

[0727] Borane tetrahydrofuran complex (1M in THF, 2.33mL, 2.33mmol) 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 (9mL) 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 (1M in THF, 2.33mL, 2.33mmol) 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 (6mL). The quenched product mixture was heated to 70°C and stirred for 3 hours. The product mixture was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel with 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%). 29 H 41 LCMS calculated for FN7O4 [M+H] + :m / z=570.3; Found:570.3

[0728] 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)

[0729] 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 give 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%). 24 H33 LCMS calculated for FN7O2 [M+H] + :m / z=470.3; Found:470.1

[0730] Intermediates 41-53

[0731] The intermediates shown in Table 5 below were prepared by procedures analogous to those described for the preparation of intermediate 40 using appropriate starting materials.

[0732] Table 5. Intermediates 41-53

[0733]

[0734]

[0735]

[0736] 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)

[0737]

[0738] Step 1. Synthesis of 2-(fluoromethyl)piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl 2-methyl ester

[0739]

[0740] LiHMDS (1M in THF, 8.97mL, 8.97mmol) was added to a solution of (S)-piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl 2-methyl ester (2.06g, 5.98mmol) in THF (24mL) at -78°C. The reactants were stirred at -78°C for 1.5h. Fluoroiodomethane (1.2mL, 12mmol) was added, and the reactants were slowly warmed to room temperature and stirred overnight. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (60mL) and extracted with EtOAc (2×60mL). The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel with a gradient of 0-30% EtOAc / hexane to give 2-(fluoromethyl)piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl 2-methyl ester (1.98g, 88%) as an oil. C8H 14 LCMS calculated value of FN2O4 [M+2H-C9H 16 O2] +:m / z=221.1; Found:221.1

[0741] Step 2. Synthesis of 1,4-bis(tert-butoxycarbonyl)-2-(fluoromethyl)piperazine-2-carboxylic acid

[0742]

[0743] Lithium hydroxide (2.97 g, 70.8 mmol) was added to a solution of 2-(fluoromethyl)piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl 2-methyl ester (2.8 g, 7.54 mmol) in THF (25 mL), methanol (25 mL) and water (25 mL) at room temperature. The reaction mixture was heated to 55 ° C and stirred overnight. The reaction mixture was quenched with 1M HCl solution (75 mL). The product mixture was transferred to a separatory funnel and extracted with DCM (2×100 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was used in the next step without purification. 1,4-bis(tert-butoxycarbonyl)-2-(fluoromethyl)piperazine-2-carboxylic acid (2.7 g, 99%) was obtained as a yellow oil. C7H 12 LCMS calculated value of FN2O4 [M+2H-C9H 16 O2] + :m / z=207.1; Found:207.0

[0744] Step 3. Di-tert-butyl 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)-dicarboxylate

[0745]

[0746] Oxalyl chloride (831 μL, 9.69 mmol) was added dropwise to a stirred solution of DMF (750 μL, 9.69 mmol) and DCM (16 mL) at 0 ° C. The reaction mixture was stirred for 10 minutes at 0 ° C. Subsequently, a solution of 1,4-bis(tert-butoxycarbonyl)-2-(fluoromethyl)piperazine-2-carboxylic acid (2.7 g, 7.45 mmol) and pyridine (904 μL, 11.2 mmol) in DCM (5 mL) was added to the reaction mixture at 0 ° C. After addition, the reaction mixture was stirred at 0 ° C for 30 minutes. The reaction mixture was then diluted with DCM (30 mL), transferred to a separatory funnel, and washed with water (2 × 30 mL) and a saturated aqueous solution of sodium chloride (30 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was dissolved in DMF (11 mL), and N, N-diisopropylethylamine (3.89 mL, 22.4 mmol) and 4-bromo-6-chloropyridazine-3-amine (1.4 g, 6.71 mmol) were added sequentially. The obtained mixture was stirred at 120 ° C overnight. The product mixture was diluted with EtOAc (150 mL) and washed with a saturated aqueous solution of sodium chloride (2 × 200 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography with a gradient of 0-100% EtOAc / hexane to obtain 2-chloro-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 ester in the form of a mixture with 4-bromo-6-chloropyridazine-3-amine. The mixture was dissolved in THF (20 mL), and di-tert-butyl dicarbonate (1.7 mL, 7.45 mmol) and 4-(dimethylamino)pyridine (120 mg, 0.97 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 flash column chromatography on silica gel with a gradient of 0-100% EtOAc / hexane to give di-tert-butyl 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)-dicarboxylate (465 mg, 13.2%) as a light yellow foamy solid. 20 H 28 LCMS calculated value of ClFN5O5 [M+H] + :m / z=472.2; Found:472.0

[0747] Step 4. tert-Butyl 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-carboxylate

[0748]

[0749] Into a 20mL scintillation vial was charged 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 ester (isomer 1) (465mg, 0.985mmol), cesium carbonate (963mg, 2.96mmol), XPhosPd G2 (77.5mg, 0.01mmol) and 3-fluoro-2-methoxyphenylboronic acid (385mg, 2.27mmol). The mixture was dissolved in 1,4-dioxane (5.8mL) and water (0.7mL). The reaction mixture was bubbled with N2 gas for 2 minutes, sealed and heated to 80°C. The reaction mixture was stirred at 80°C for 2 hours. The product mixture was diluted with EtOAc (50mL) and washed with water (100mL). 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 0-100% EtOAc / hexane to afford tert-butyl 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-carboxylate (332 mg, 73%). 22 H 26 LCMS calculated for F2N5O4 [M+H] + :m / z=462.2; Found:462.1

[0750] Step 5. 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

[0751]

[0752] Borane tetrahydrofuran complex (1M, 2.97mL, 2.97mmol) was added to a solution of tert-butyl 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-carboxylate (342mg, 0.742mmol) in THF (5mL) at room temperature. The reaction mixture was heated to 60°C. The reaction mixture was stirred at 60°C for 2 hours. The reaction mixture was cooled to 0°C and slowly quenched with MeOH (3mL). The reaction mixture was diluted with EtOAc (60mL). The diluted reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate (2×60mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was dissolved in THF (5mL) and MeOH (2mL). Acetic acid (1.27mL, 22.3mmol) and sodium cyanoborohydride (466mg, 7.42mmol) were added to the reaction mixture in sequence at room temperature. The reaction mixture was refluxed at 80°C for 16 hours. The product mixture was cooled to room temperature and diluted with EtOAc (100mL). The diluted reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate (2×100mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was dissolved in THF (5mL). Di-tert-butyl dicarbonate (340μL, 1.48mmol) and 4-(dimethylamino)pyridine (11mg, 0.09mmol) were added in sequence. The reaction mixture was stirred at room temperature for 2 hours. The product mixture was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel with a gradient of 0-100% EtOAc / hexanes to afford 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 (270 mg, 66%) as a dark oil. 27 H 36 LCMS calculated value of F2N5O5 [M+H] + :m / z=548.3; Found:548.2

[0753] Step 6. Chiral separation of 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

[0754]

[0755] A racemic mixture of 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 (270 mg) was separated by chiral separation (Lux Cellulose-1, 30 mL / min of 65:17.5:17.5 hexanes / IPA / MeOH) to give 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 ester (98 mg, peak A, isomer 1, 36%) and 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 ester (111 mg, peak B, isomer 2, 41%). 27 H 36 LCMS calculated value of F2N5O5 [M+H] + :m / z=548.3; Found:548.2

[0756] 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)

[0757]

[0758] Hydrochloric acid (4M in 1,4-dioxane, 0.52 mL, 2.09 mmol) was added to a solution of tert-butyl 2-(3-fluoro-2-methoxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (Isomer 2) (62.1 mg, 0.14 mmol) in DCM (2.8 mL) at room temperature. The reaction was stirred overnight. The product mixture was concentrated under reduced pressure to give the HCl salt 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) (58 mg, 100%) as a brown solid. 17 H 20 LCMS calculated for F2N5O [M+H] + :m / z=348.2; Found:348.0

[0759] Step 8. 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)

[0760]

[0761] 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 a saturated aqueous solution of 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 flash column chromatography on silica gel with 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%). 29 H 40 LCMS calculated for F2N7O4 [M+H] + :m / z=588.3; found: 588.2.

[0762] 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)

[0763] Boron tribromide (119 μL, 1.25 mmol) was added to a stirred solution of 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) (74 mg, 0.125 mmol) in DCM (4 mL) at 0°C. The reaction was warmed to room temperature and stirred for 12 hours. 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 under reduced pressure to give (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) (51 mg, 86%). 23 H 30 LCMS calculated for F2N7O2 [M+H] + :m / z=474.2; Found: 474.2.

[0764] Intermediate 56

[0765] The intermediates shown in Table 6 below were prepared by procedures analogous to those described for the preparation of intermediate 55 using appropriate starting materials.

[0766] Table 6. Intermediate 56

[0767]

[0768] 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

[0769]

[0770] 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

[0771]

[0772] To a vial containing cis-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (206 mg, 0.96 mmol) was added DCM (4.80 mL) and pyridine (0.190 mL, 2.40 mmol). The reaction was cooled to 0 ° C and triphosgene (186 mg, 0.630 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was diluted in DCM and subsequently washed with 1N HCl aqueous solution. The layers were separated and the aqueous phase was extracted with additional DCM. The organic layers were combined and 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-trien-4-yl]phenol; dihydrochloride (180 mg, 0.480 mmol) and triethylamine (0.340 mL, 2.40 mmol) were added. The reaction was stirred at room temperature overnight. The crude residue was purified by prep-HPLC (Waters CSH-C18, 23.5-43.5% MeCN / water (with 0.1% TFA) over 5 min) to give the Boc-intermediate as a brown oil. The residue was dissolved in DCM (4.80 mL) and 2,2,2-trifluoroacetic acid (1.10 mL, 14.4 mmol) was added and the reaction was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure to provide ((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 (119.47 mg, 45% yield) as a TFA salt. The material was used without further purification. 22 H 29 LCMS calculated for FN7O2 [M+H] + :m / z=442.2; found: 442.1.

[0773] 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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0774] A solution of pyridine sulfur trioxide (94.5 mg, 0.590 mmol) in DMSO (0.500 mL) was added dropwise to a vial containing a solution of 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 on ice. After the addition was complete, the reaction 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 min. Acetic acid (0.170 mL, 2.97 mmol) was added, the reaction was cooled to 0°C and sodium triacetoxyborohydride (167.86 mg, 0.790 mmol) was added in one portion. The reaction was stirred at 0°C until completion. Upon completion, water was added and the reaction was stirred for 1 hour. The reaction mixture was filtered and the filtrate was purified by prep-HPLC (Waters CSH-C18, 5 μM, 30×100 mm, 9.5-19.5% MeCN / water with 0.1% TFA over 5 min) 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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione as a TFA salt (36.0 mg, 32% yield). 1H NMR(400MHz,MeOD)7.46(d,J=8.4Hz,1H),7.38-7.28(m,4H),7.20(s,1H),7.02(td,J=8.1,4.8Hz,1H),5.14(dd,J=13.3,5.2 Hz,1H),4.52-4.32(m,2H),4.20(d,J=12.8Hz,1H),3.82(d,J=12.4Hz,2H),3.79-3.70(m,2H),3.62(d,J=11.8Hz,2H),3.39(q ,J=8.1Hz,2H),3.34-3.27(m,6H),3.18-3.12(m,2H),3.05(t,J=12.5Hz,1H),2.98-2.84(m,5H),2.79(dq,J=17.6,2.3Hz,1H ), 2.51(qd,J=13.1,4.6Hz,1H),2.22-2.08(m,2H),1.95(d,J=12.8Hz,2H),1.52(q,J=11.2Hz,2H),1.15(s,3H),1.03(s,3H). C 41 H 50 FN 10 LCMS calculated value of O5 [M+H] + :m / z=781.4; found: 781.3.

[0775] Example 2-36:

[0776] The examples shown in Table 7 below were prepared as TFA salts by the method used to prepare Example 1 using appropriate intermediates and starting materials.

[0777] Table 7. Examples 2-36

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788]

[0789] 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]hexan-3-yl)methyl)-3-fluoropiperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Isomers 1 and 2)

[0790]

[0791] Step 1. Tert-butyl (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-carboxylate

[0792]

[0793] A solution of acetic acid (100 μL, 1.70 mmol), (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 (111 mg, 0.283 mmol, Intermediate 2), (1R,5S,6r)-tert-butyl 6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (90.0 mg, 0.424 mmol) and N,N-diisopropylethylamine (197 μL, 1.13 mmol) in DMF (1.00 mL) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (180 mg, 0.849 mmol) was added and the reaction was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (3.00 mL) and washed with water (2×3 mL). The organics were dried over MgSO 4 , filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel using a gradient of 0-10% MeOH / DCM to give (1R,5S)-6-[[(10S)-4-(3,5-difluoro-2-hydroxyphenyl)-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradec-2,4,6-trien-12-yl]methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (140 mg, 96% yield). 26 H 33 LCMS calculated for F2N6O3 [M+H] + :m / z=515.3; found: 515.1.

[0794] 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

[0795]

[0796] A solution of 4N HCl in 1,4-dioxane (1.17 mL, 37.9 mmol) was added to a solution of (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 ester (140 mg, 0.272 mmol) in DCM (1.00 mL). The reactants were stirred at room temperature for 1 hour. The mixture was concentrated to give the title compound (120 mg, 91% yield) as an HCl salt. The material was used in the subsequent step without further purification. 21 H 25 LCMS calculated for F2N6O [M+H] + :m / z=415.2; Found:415.1

[0797] Step 3. (3R,4R)-1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3-fluoropiperidin-4-yl)methyl 4-methylbenzenesulfonate (Isomers 1 and 2)

[0798]

[0799] To a mixture of ((3R,4R)-1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3-fluoropiperidin-4-yl)methyl 4-methylbenzenesulfonate (82.0 mg, 0.218 mmol, Intermediate 22) in pyridine (1.07 mL, 13.3 mmol) was added tosyl chloride (83.3 mg, 0.440 mmol). The mixture was stirred at room temperature for 1 hour. Additional tosyl chloride was added every 2 hours until the starting material was consumed. The mixture was diluted with DCM and the organic phase was washed with water. The combined organics were dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel eluting with a gradient of 0-100% EtOAC / DCM to afford rac-4-methyl-benzenesulfonic acid ((3R,4R)-1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3-fluoropiperidin-4-yl)methyl ester (110 mg, 95% yield). 26 H 29 LCMS calculated for FN3O6S [M+H] + :m / z=530.2; measured value: 530.2.

[0800] 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-trien-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)

[0801] 2-[(10S)-12-[[(1S,5R)-3-azabicyclo[3.1.0]hex-6-yl]methyl]-1,5,6,8,12-pentaazatricyclo-[8.4.0.02,7]tetradeca-2,4,6-trien-4-yl]-4,6-difluorophenol; dihydrochloride (20.0 mg, 41.0 μmol), 4-methyl-benzenesulfonic acid ((racemic-3R,4R) A solution of -1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3-fluoro-piperidin-4-yl)methyl ester (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) was stirred at 130 °C for 1 hour. The crude mixture reaction mixture was diluted with DMSO (15.0 mL), filtered and the filtrate was purified by prep-HPLC on a C18 column (7.6-27.6% MeCN / 0.1% TFA (aq), pH=2) to afford the title compound (2.50 mg, 7.6% yield, Peak 2, Isomer 2, Example 38 5790) and the title compound (0.6 mg, 1.9%, Peak 1, Isomer 1, Example 37 5789) as white solids as their TFA salts. 40 H 45 LCMS calculated for F3N9O4 [M+H] + :m / z=772.4; found: 772.1.

[0802] Examples 39-41:

[0803] The examples shown in Table 8 below were prepared as TFA salts by the methods used to prepare Examples 37 and 38 using appropriate intermediates and starting materials.

[0804] Table 8. Examples 39-41

[0805]

[0806] Examples 42 and 43: 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-dimethylpiperazin-1-yl)methyl)-3-fluoropiperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Isomers 1 and 2)

[0807]

[0808] [(10S)-4-(3,5-difluoro-2-hydroxyphenyl)-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradeca-2(7),3,5-trien-12-yl]-[(2R,6S)-2,6-dimethylpiperazin-1-yl]methanone; 2,2,2-trifluoroacetic acid (14.8 mg, 20.0 μmol, prepared in a manner similar to Example 1, Step 1 using appropriate starting materials), 4-methylbenzene-sulfonic acid (( A mixture of rac-3R,4R)-1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3-fluoropiperidin-4-yl)methyl ester (14.8 mg, 30.0 μmol, Examples 37 and 38, Step 3), N,N-diisopropylethylamine (10 μL, 90.0 μmol) and sodium iodide (6.45 mg, 40.0 μmol) in NMP (0.200 mL) was stirred at 120° C. for 1 hour. The product was analyzed by prep-HPLC (Waters The mixture was purified by CSH-C18, 5 μM, 30×100 mm, 6.1-26.1% MeCN / water (containing 0.1% TFA) over 5 min to give 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-dimethylpiperazin-1-yl)methyl)-3-fluoropiperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; bis(trifluoroacetic acid) (0. 600 mg, 3.40% yield) (peak 1, isomer 1, Example 42, 5567) and 3-(6-((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-dimethylpiperazin-1-yl)methyl)-3-fluoropiperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; bistrifluoroacetic acid (5.40 mg, 30.7% yield) (peak 2, isomer 2, Example 43, 5568). C 41 H 48 F3N 10 LCMS calculated value of O5 [M+H] + :m / z=817.4; found: 817.2.

[0809] Example 44

[0810] The examples shown in Table 9 below were prepared as TFA salts by the methods used to prepare Examples 42 and 43 using appropriate intermediates and starting materials.

[0811] Table 9. Example 44

[0812]

[0813] 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

[0814]

[0815] Step 1: (R)-5-((9H-fluoren-9-yl)methyl)8-(tert-butyl)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)-dicarboxylate

[0816]

[0817] A mixture of (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 ester (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 1,4-dioxane (4.00 mL) and water (0.500 mL) was 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, and the combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue is suspended in a mixture of 1,4-dioxane (4.00mL) and water (0.500mL), and 9-fluorenylmethoxycarbonyl chloride (401mg, 1.55mmol) is added, followed by sodium bicarbonate (355mg, 4.23mmol). After stirring at room temperature for 4 hours, another portion of 9-fluorenylmethoxycarbonyl chloride (401mg, 1.55mmol) and sodium bicarbonate (355mg, 4.23mmol) is added. The reactant is stirred at room temperature overnight. The reaction mixture is diluted with DCM and water. Separate each layer and through Na2SO4 dry the combined organic matter, filter and concentrate under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with a gradient of 0-100% EtOAc / hexanes to afford (R)-5-((9H-fluoren-9-yl)methyl)8-(tert-butyl)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)-dicarboxylate (492 mg, 81% yield). 50 H 44 LCMS calculated for F2N5O7 [M+H] + :m / z=864.3; Found: 864.3.

[0818] Step 2: (R)-(9H-Fluoren-9-yl)methyl 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-carboxylate

[0819]

[0820] (R)-5-((9H-Fluoren-9-yl)methyl)8-(tert-butyl)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)-dicarboxylate (421 mg, 0.487 mmol) was dissolved in DCM (4.87 mL) and treated with a 4N solution of HCl in 1,4-dioxane (0.610 mL, 2.44 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give crude (R)-(9H-fluoren-9-yl)methyl 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-carboxylate (407 mg) as the HCl salt. The material was used without further purification. 45 H 36 LCMS calculated value of F2N5O5 [M+H] + :m / z=764.3; found: 764.2.

[0821] 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

[0822]

[0823] To a vial containing tert-butyl (3R,5R)-3,5-dimethylpiperazine-1-carboxylate (82.0 mg, 0.380 mmol) was added DCM (1.90 mL) and pyridine (0.08 mL, 0.96 mmol) at 0°C, followed by triphosgene (68.1 mg, 0.23 mmol). The reaction was stirred at room temperature for 1 hour, after which the reaction was diluted in DCM and 1N aqueous HCl. The layers were separated, and the combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was suspended in DCM (1.90 mL) and crude (R)-(9H-fluoren-9-yl)methyl 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-carboxylate; dihydrochloride (160 mg, 0.190 mmol) and triethylamine (0.130 mL, 0.960 mmol) were added. The reaction was stirred at room temperature for 48 hours. The crude reaction mixture was diluted in EtOAc and the organic phase was washed with saturated brine solution. The combined organics were dried over NaSO, filtered and concentrated under reduced pressure. The crude residue was dissolved in MeOH (3.00 mL) and water (1.00 mL) and lithium hydroxide (20 equiv) were added. The reaction was stirred at 85°C for 12 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was purified by prep-HPLC (Waters CSH-C18, 5 μM, 30×100 mm, 25.6-45.6% MeCN / water (containing 0.1% TFA) over 5 min) to afford the boc-intermediate. 2,2,2-Trifluoroacetic acid (0.439 mL) was added to a solution of the Boc-intermediate in DCM (1.90 mL). The reaction was stirred at room temperature. After completion, the reaction mixture was concentrated under reduced pressure to afford ((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 (50.0 mg, 46% yield) as a TFA salt. The material was used without further purification. 22 H 28 LCMS calculated for F2N7O2 [M+H] + :m / z=460.2; found: 460.1.

[0824] 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]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0825] The title compound was prepared using a procedure analogous to that described for Preparative Example 1, Step 2, substituting ((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)((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 for ((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. 41 H 49 F2N 10 LCMS calculated value of O5 [M+H] + :m / z=799.4; found: 799.2.

[0826] Examples 46-47:

[0827] The examples shown in Table 10 below were prepared as TFA salts by the method used to prepare Example 45 using appropriate intermediates and starting materials.

[0828] Table 10. Examples 46-47

[0829]

[0830] 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]pyridazine-8-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0831]

[0832] Step 1. Piperidine-4-carboxaldehyde

[0833]

[0834] A solution of 4N HCl in 1,4-dioxane (20 mL, 80 mmol) was added dropwise to a solution of 1-Boc-piperidine-4-carboxaldehyde (601 mg, 2.82 mmol) in 1,4-dioxane (20 mL). The reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the HCl salt of the title compound hydrochloride as a white solid (398 mg, 94% yield).

[0835] 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]pyridazine-8-carbonyl)piperidine-4-carbaldehyde

[0836]

[0837] To a solution of piperidine-4-carboxaldehyde; hydrochloride (111 mg, 0.740 mmol) and pyridine (0.120 mL, 1.48 mmol) in DCM (2.50 mL) was added a solution of triphosgene (82.0 mg, 0.28 mmol) in DCM (0.5 mL) at 0 ° C. The reaction was stirred at 0 ° C for 1 hour, then warmed to room temperature and stirred for 3 hours. The reaction was poured into 1N HCl aqueous solution (5.00 mL), and the aqueous phase was extracted with DCM (2×3 mL). The combined organics were dried over MgSO 4 , filtered and concentrated under reduced pressure. The crude residue was dissolved in DCM (3 mL) and 2,4-difluoro-6-[(10R)-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradeca-2(7),3,5-trien-4-yl]phenol; dihydrochloride (73.0 mg, 0.180 mmol, Intermediate 2) and triethylamine (0.10 mL, 0.74 mmol) were added. The reactants were stirred at room temperature for 1 hour. The reaction mixture was diluted in methanol (15 mL), filtered, and the filtrate was purified by prep-HPLC on a C18 column (11.5-31.5% MeCN / 0.1% TFA (aq.), pH = 2) to give the TFA salt of the title compound as a light yellow oil (27.0 mg, 26% yield). 22 H 25 LCMS calculated for F2N6O3 [M+H] + :m / z=459.2; found: 459.0.

[0838] Step 3: 3-(1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

[0839]

[0840] To a vial containing tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]piperazine-1-carboxylate (136.0 mg, 0.320 mmol, Intermediate 23) was added methanol (1.50 mL) and 4N HCl in dioxane (1.50 mL, 6.00 mmol). The reaction was stirred for 1.5 hours. The reaction was condensed to give 3-(1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione; hydrochloride salt (115.0 mg, 99% yield) as an off-white solid. 17 H 21 LCMS calculated for N4O3 [M+H] + :m / z=329.2; found: 329.1.

[0841] 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]pyridazine-8-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0842] A solution of (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) was 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 prep-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). 39 H 45 F2N 10 LCMS calculated value of O5 [M+H] + :m / z=771.4; found: 771.2.

[0843] 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

[0844]

[0845] To a solution of 3-[5-[2-(hydroxymethyl)morpholin-4-yl]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione (86.3 mg, 0.240 mmol, Intermediate 26) in DMSO (1.50 mL) was added triethylamine (0.33 mL, 2.40 mmol). The reaction was cooled to 0° C. and a solution of sulfur trioxide-pyridine (232.0 mg, 1.46 mmol) in DMSO (1.0 mL) was added dropwise. After warming to room temperature and stirring for 3 hours, a solution of 2-[(10S)-12-[[(1S,5R)-3-azabicyclo[3.1.0]hex-6-yl]methyl]-1,5,6,8,12-pentaazatricyclo-[8.4.0.02,7]tetradeca-2(7),3,5-trien-4-yl]-4,6-difluorophenol; 2,2,2-trifluoroacetic acid (77.1 mg, 0.120 mmol, Examples 37 and 38, Step 1) in MeCN (2.50 mL) was added. Acetic acid (0.55 mL, 9.61 mmol) was added at 0°C. After 10 minutes on ice, sodium triacetoxyborohydride (256.0 mg, 1.21 mmol) was added, and the reaction mixture was warmed to room temperature and stirred overnight. Upon completion, water was added and diluted in DMSO. The reaction mixture was filtered and the filtrate was purified by prep-HPLC (Waters CSH Phenyl-hexyl, 5 μM, 30×100 mm, 8.0-20.0% MeCN / water with 0.1% TFA over 5 min) to afford 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 as a TFA salt (35.2 mg, 13%). 1H NMR (400MHz, DMSO) δ10.99(s,1H),9.76(s,1H),7.95(s,1H),7.62(s,1H),7.49(d,J=8.4Hz,1H),7.39(d,J=15.7 Hz,2H),7.30-7.25(m,1H),7.23(d,J=2.3Hz,1H),5.09(dd,J=13.3,5.1Hz,1H),4.46(s,2H),4.36(d,J=16.9Hz,2 H),4.23(d,J=16.8Hz,2H),4.05-3.94(m,3H),3.80-3.60(m,9H),3.44(d,J=36.4Hz,4H),3.30(d,J=11.3Hz,3H), 3.18-2.84(m,5H),2.77(t,J=10.9Hz,1H),2.70-2.53(m,2H),2.42-2.31(m,1H),2.04-1.87(m,3H),1.52(s,1H). C 39 H 44 LCMS calculated for F2N9O5 [M+H] + :m / z=756.3; found: 756.2.

[0846] Examples 50-53:

[0847] The examples shown in Table 11 below were prepared as TFA salts by the method used to prepare Example 49 using appropriate intermediates and starting materials.

[0848] Table 11. Examples 50-53

[0849]

[0850]

[0851] 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

[0852]

[0853] Step 1: ((1r,4r)-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclohexyl)methanol

[0854]

[0855] Toluenesulfonic acid (36.0 mg, 0.209 mmol) was added to a solution of ((1r, 4r)-cyclohexane-1,4-diyl) dimethanol (2.00 g, 13.9 mmol) in DCM (30 mL) at 0 ° C. The reactants were stirred at 0 ° C. for 30 min, then warmed to room temperature and stirred overnight. The crude reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate, and the layers were separated. The organic matter was washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography with a gradient elution of 0-100% EtOAc / hexane to give ((1r, 4r)-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclohexyl)methanol (850 mg, 27% yield) as a clear oil. Note: The product did not ionize on LCMS. The intermediate was used directly in the next step.

[0856] Step 2: (1r,4r)-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclohexane-1-carbaldehyde

[0857]

[0858] A solution of ((1r, 4r) -4- (((tetrahydro -2H- pyrans -2- yl) oxy) methyl) cyclohexyl) methanol (286 mg, 1.25 mmol) and Dess-Martin periodinane (706 mg, 1.66 mmol) in DCM (12.5 mL) was stirred at room temperature for 2.5 hours. The crude reaction mixture was diluted with DCM, and a saturated aqueous solution of sodium bicarbonate was added. The layers were separated, and the organic matter was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give crude (1r, 4r) -4- (((tetrahydro -2H- pyrans -2- yl) oxy) methyl) cyclohexane -1- carbaldehyde as a white solid. The substance can be used in subsequent steps without further purification. Note: The product will not ionize. Used directly in the next step.

[0859] 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

[0860]

[0861] The title compound was prepared using a procedure analogous to that described for the preparation of Example 48, Step 4, substituting crude (1r,4r)-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclohexane-1-carbaldehyde for (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. 30 H 43 LCMS calculated value of N4O5 [M+H] + :m / z=539.3; Found: 539.3.

[0862] Step 4: 3-(6-(4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0863]

[0864] 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) was added p-TSOH HO (1.50 mg, 0.01 mmol) in a 1:1 mixture of DCM (0.250 mL) and methanol (0.250 mL). 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 prep-HPLC (Waters CSH Phenyl-hexyl, 5 μM, 30×100 mm, 5.8-25.8% MeCN / water with 0.1% TFA over 5 min) 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). 25 H 35 LCMS calculated for N4O4 [M+H] + :m / z=455.3; Found:455.2

[0865] 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

[0866] The title compound was prepared using a procedure analogous to that described for the preparation of Example 49, substituting 3-(6-(4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione for 3-[5-[2-(hydroxymethyl)morpholin-4-yl]-3-oxo-1H-isoindol-2-yl]-piperidine-2,6-dione and Intermediate 2 for 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-trien-4-yl]-4,6-difluorophenol; 2,2,2-trifluoroacetic acid. 40 H 48 LCMS calculated for F2N9O4 [M+H] + :m / z=756.4; found: 756.3.

[0867] 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]pyridazine-8-carbonyl)-4-fluoropiperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0868]

[0869] Step 1: (S)-tert-Butyl 4-(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-carboxylate

[0870]

[0871] A mixture of N,N-diisopropylethylamine (50.0 μL, 0.310 mmol), 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (35.1 mg, 90.0 μmol), 2,4-difluoro-6-[(10R)-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradec-2,4,6-trien-4-yl]phenol; dihydrochloride (33.2 mg, 80.0 μmol, Intermediate 2) and 4-fluoro-1-[(2-methylprop-2-yl)oxycarbonyl]piperidine-4-carboxylic acid (19.0 mg, 80.0 μmol) in DMF (200 μL) was stirred at room temperature for 2 h. The mixture was diluted with DCM, washed with water, concentrated and purified by flash column chromatography on silica gel (0-10% MeOH / DCM) to give (S)-tert-butyl 4-(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-carboxylate (35.0 mg, 83% yield). 26 H 32 LCMS calculated for F3N6O4 [M+H] + :m / z=549.2; found: 549.1.

[0872] 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]pyridazin-8-yl)(4-fluoropiperidin-4-yl)methanone

[0873]

[0874] (S)-tert-Butyl 4-(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-carboxylate (35.0 mg, 60.0 μmol) was treated with 4N hydrochloric acid in 1,4-dioxane (0.56 mL, 18.2 mmol) in DCM (1.00 mL) at room temperature for 1 h. The mixture was concentrated under reduced pressure to give (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)(4-fluoropiperidin-4-yl)methanone; dihydrochloride (16.0 mg, 48% yield). 21 H 24 LCMS calculated for F3N6O2 [M+H]+ :m / z=449.2; found: 449.0.

[0875] 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

[0876] 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 triethylamine (80.0 μL, 0.550 mmol) was added. Pyridine sulfur trioxide (29.3 mg, 0.180 mmol) in DMSO (500 μL) was added dropwise and the reaction 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-trien-12-yl]-(4-fluoropiperidin-4-yl)methanone; dihydrochloride (16.0 mg, 30.0 μmol) and acetic acid (50 μL, 0.920 mmol) were added to 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 prep-HPLC (Waters CSHCl 8, 5 μΜ, 30 x 100 mm, 7.7-27.7% MeCN / water with 0.1% TFA over 5 min) to afford 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 as a TFA salt (6.20 mg, 26% yield). 40 H 45 LCMS calculated for F3N9O5 [M+H] + :m / z=788.4; found: 788.1.

[0877] 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

[0878]

[0879] Step 1: (1s,4s)-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclohexane-1-carboxylic acid

[0880]

[0881] To a 100 mL round-bottom flask was added cis-4-(hydroxymethyl)cyclohexanecarboxylic acid (2.24 g, 14.2 mmol), DCM (33.0 mL) and p-TSOH HO (49.0 mg, 0.260 mmol). The reactants were heated to 40 ° C to help partially dissolve the mixture. The reactants were cooled to -78 ° C, and a solution of 3,4-dihydro-2H-pyran (1.41 mL, 15.5 mmol) in DCM (33.0 mL) was added dropwise via an addition funnel over 35 minutes. The reactants were allowed to warm to room temperature. After 4.5 hours, the reactants were quenched with 30.0 mL of saturated sodium bicarbonate and stirred vigorously for 10 minutes. The solution was poured into a separatory funnel with more saturated sodium bicarbonate and DCM. The organic layer was separated, dried and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (120 g) eluting with a 0-100% EtOAC / hexanes gradient to afford (1s,4s)-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclohexane-1-carboxylic acid (1.00 g, 29% yield) as a clear oil. Note: The product was not ionized and was used directly in the next step without additional purification.

[0882] Step 2: ((1s,4s)-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclohexyl)methanol

[0883]

[0884] (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. The reaction was stirred at 0°C for 10 minutes and then allowed to slowly warm to room temperature. After 5 hours, the reaction was quenched with MeOH, concentrated under reduced pressure, then dissolved in EtOAc and poured into water. The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic layers were washed with water, then with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give ((1s,4s)-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclohexyl)methanol (75.5 mg, 59% yield) as a clear oil. Note: The product is not ionized and can be used directly in the next step without further purification.

[0885] 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

[0886]

[0887] ((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 was cooled to 0 ° C. and a solution of pyridine sulfur trioxide (107 mg, 0.670 mmol) in DMSO (1.20 mL) was added dropwise. After 3.5 hours at RT, 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. The reaction mixture was stirred at room temperature for 15 minutes, followed by the addition of sodium triacetoxyborohydride (92.9 mg, 0.44 mmol). After 3 hours, the reaction was quenched with water, diluted in 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 afford 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 a TFA salt (white powder). 30 H 43 LCMS calculated value of N4O5 [M+H] + :m / z=539.3; found: 539.2.

[0888] Step 4: 3-(6-(4-(((1s,4s)-4-(hydroxymethyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0889]

[0890] To 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 (33.0 mg, 0.060 mmol) was added 1,4-dioxane (800 μL) and 4N HCl in dioxane (420 μL, 1.68 mmol). After 1.5 hours, the volatiles were removed in vacuo to give 3-(6-(4-(((1s,4s)-4-(hydroxymethyl)cyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (44.0 mg, quantitative yield) as the HCl salt of a white solid.25 H 35 LCMS calculated for N4O4 [M+H] + :m / z=455.3; Found:455.1.3

[0891] 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

[0892] 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) and triethylamine; TEA (50.0 μL, 0.390 mmol). The reaction was cooled to 0°C and sulfur trioxide (42.0 mg, 0.26 mmol) in DMSO (0.5 mL) was added dropwise. After 3 hours 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 stirred for 80 minutes. Sodium triacetoxyborohydride (48.96 mg, 0.23 mmol) was then added and the reaction was stirred at RT. After stirring overnight, the reaction was quenched with water, diluted in 15 mL of DMSO, and directly purified using an automated LCMS purification system (10.4-23.4% ACN / water (0.1% TFA) over 5 min, Waters CSH-C18 column) to afford 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 a white solid in the form of a TFA salt. 40 H 48 LCMS calculated for F2N9O4 [M+H] + :m / z=756.4; found: 756.2.

[0893] 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]pyridazine-8-carbonyl)-2,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0894]

[0895] The title compound was prepared as a TFA salt using a procedure similar to that described for Intermediate 4, Steps 1-10, using appropriate starting materials and intermediates, substituting (2S,5R)-tert-butyl 2,5-dimethylpiperazine-1-carboxylate for (3R,5S)-tert-butyl 3,5-dimethylpiperazine-1-carboxylate in Step 9 and Example 1. 42 H 52 FN 10 LCMS calculated value of O5 [M+H] + :m / z=795.4; found: 795.1.

[0896] 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

[0897]

[0898] The title compound was prepared as a TFA salt using procedures similar to those described for Example 54, steps 1-5, substituting Intermediate 1 for Intermediate 2 in step 5. 40 H 49 LCMS calculated value of FN9O4 [M+H] + :m / z=738.4; found: 738.2.

[0899] 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]pyridazine-8-carbonyl)-3,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Isomer 1)

[0900]

[0901] The title compound was prepared as a TFA salt using a procedure similar to that described for Example 1 using appropriate starting materials and intermediates. 43 H 53 F2N 10 LCMS calculated value of O5 [M+H] + :m / z=827.4; found: 827.2.

[0902] Example 60: 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 (Isomer 1)

[0903]

[0904] The title compound was prepared as a TFA salt using a procedure similar to that described for Example 1 using appropriate starting materials and intermediates. 43 H 54 FN 10 LCMS calculated value of O5 [M+H] + :m / z=809.4; found: 809.2.

[0905] 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]pyridazine-8-carbonyl)-3,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Isomer 2)

[0906]

[0907] The title compound was prepared as a TFA salt using a procedure similar to that described for Example 1 using appropriate starting materials and intermediates. 43 H 53 F2N 10 LCMS calculated value of O5 [M+H] + :m / z=827.4; found: 827.1.

[0908] Example 62: 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 (Isomer 2)

[0909]

[0910] The title compound was prepared as a TFA salt using a procedure similar to that described for Example 1 using appropriate starting materials and intermediates. 43 H 54 FN 10 LCMS calculated value of O5 [M+H] + :m / z=809.4; Found: 809.4.

[0911] 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]pyridazine-8-carbonyl)-3,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Isomer 2)

[0912]

[0913] The title compound was prepared as a TFA salt using a procedure similar to that described for Example 1 using appropriate starting materials and intermediates. 42 H 52 C1N 10 LCMS calculated value of O5 [M+H] + :m / z=811.4; found: 811.0.

[0914] 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]pyridazine-8-carbonyl)-3,5-dimethyl-piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Isomer 2)

[0915]

[0916] The title compound was prepared as a TFA salt using a procedure similar to that described for Example 1 using appropriate starting materials and intermediates. 42 H 51 F2N 10 LCMS calculated value of O5 [M+H] + :m / z=813.4; found: 813.1.

[0917] 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

[0918]

[0919] 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]pyridazin-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 prep-HPLC (Waters CSH-C18, 5 μM, 30×100 mm, 8.1-28.1% MeCN / water with 0.1% TFA over 5 min) to afford (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 a TFA salt (235 mg, 24%). 1H NMR(400MHz,MeOD)δ7.46(s,1H),7.39-7.28(m,5H),7.03(s,1H),6.27(t,J=54.6Hz ,1H),5.13(d,J=13.4Hz,1H),4.38(s,3H),4.18(s,1H),4.01(d,J=9.9Hz,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=17.6Hz, 1H), 2.49 (q, J = 13.8Hz, 1H), 2.16 (s, 2H), 1.91 (d, J = 12.6Hz, 2H), 1.66-1.37 (m, 9H). C 42 H 50 F3N 10 LCMS calculated value of O5 [M+H] + :m / z=831.4; found: 831.3.

[0920] Examples 66-70

[0921] Examples 66-70 shown in Table 12 below were prepared as TFA salts by the method used to prepare Example 65 using appropriate intermediates and starting materials.

[0922] Table 12. Examples 66-70

[0923]

[0924]

[0925]

[0926] 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]pyridazine-8-carbonyl)-2,6-dimethylpiperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0927]

[0928] Step 1. tert-Butyl (2R,4r,6S)-4-(hydroxymethyl)-2,6-dimethylpiperidine-1-carboxylate

[0929]

[0930] Borane tetrahydrofuran complex (1M, 1.65mL, 1.65mmol) was added to a solution of (2R, 4r, 6S)-1-(tert-butyloxycarbonyl)-2,6-dimethylpiperidine-4-carboxylic acid (170.0mg, 0.66mmol) in THF (3.3mL) at 0°C. The reaction mixture was warmed to room temperature overnight. The reaction mixture was cooled to 0°C and quenched with MeOH (2mL). The reaction mixture was directly condensed. The residue was dissolved in water (30mL) and EtOAc (30mL). The aqueous layer was extracted with EtOAc (2×30mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl (2R, 4r, 6S)-4-(hydroxymethyl)-2,6-dimethylpiperidine-1-carboxylate (158mg, 98%) as a clear oil. CH 18 LCMS calculated value of NO [M+H-C5H9O2] + :m / z=144.1; Found:144.0

[0931] Step 2. ((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)methyl benzoate

[0932]

[0933] Benzoyl chloride is added to a stirred solution of (2R, 4r, 6S) -4- (hydroxymethyl) -2,6- dimethylpiperidine -1- carboxylic acid tert-butyl ester (188 mg, 0.77 mmol), triethylamine (118 μL, 0.85 mmol) and 4- (dimethylamino) pyridine (11 mg, 0.09 mmol) in DCM (2 mL). The reaction mixture is stirred at room temperature for 6 hours. The product mixture is diluted with EtOAc (40 mL) and washed with water (30 mL) and a saturated solution of sodium chloride (2 × 30 mL). The organic layer is dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue is dissolved in DCM (6 mL). Hydrochloric acid (4 M in 1,4-dioxane, 1.9 mL, 7.7 mmol) is added to the reaction mixture. The reaction mixture is stirred at room temperature overnight. The product mixture was concentrated under reduced pressure to give the HCl salt of ((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)methyl benzoate (220 mg, 100%) as a white powder. 15 H 22 LCMS calculated value of NO2 [M+H] + :m / z=248.2; Found:248.1

[0934] Step 3. ((2R,4r,6S)-1-(chlorocarbonyl)-2,6-dimethylpiperidin-4-yl)methyl benzoate

[0935]

[0936] Triphosgene (132 mg, 0.45 mmol) was added to a stirred solution of ((2R, 4r, 6S)-2,6-dimethylpiperidin-4-yl)methyl benzoate (330 mg, 1.16 mmol) and pyridine (0.47 μL, 5.8 mmol) in DCM (5.8 mL) at 0 ° C. The reaction mix...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof; wherein R1 is halogen, 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 3-7 membered cycloalkyl group, a 4-7 membered heterocycloalkyl group, an aryl group or a heteroaryl group; Ring A2 is a 3-7 membered cycloalkyl group, a 4-7 membered heterocycloalkyl group, an aryl group or a heteroaryl group; X1 is CH2CO, CH=CH (when X2=CO) or N=CH (when X2=CO); and X2 is CH2CO, CH=CH (when X1=CO) or N=CH (when X1=CO).

2. The compound according to claim 1, wherein R1 is halogen.

3. A compound according to claim 1 or claim 2, wherein R1 is F.

4. A compound according to any one of the preceding claims, wherein n is 1.

5. The compound according to any one of claims 1 to 3, wherein n is 2.

6. The compound according to any one of claims 1 to 3, wherein n is 3.

7. A compound according to any one of the preceding claims, wherein each R2 is F.

8. A compound according to any one of claims 1 to 6, wherein each R2 is H.

9. A compound according to any one of the preceding claims, wherein m is 1.

10. The compound according to any one of claims 1 to 8, wherein m is 2.

11. The compound according to any one of claims 1 to 8, wherein m is 3.

12. The compound according to any one of claims 1 to 8, wherein m is 4.

13. The compound according to any one of claims 1 to 8, wherein m is 5.

14. The compound according to any one of claims 1 to 8, wherein m is 6.

15. A compound according to any one of the preceding claims, wherein each R3 is H.

16. A compound according to any one of the preceding claims, wherein R4 is H.

17. A compound according to any one of claims 1 to 15, wherein R4 is D.

18. A compound according to any one of claims 1 to 15, wherein R4 is C 1-6 alkyl.

19. A compound according to any one of claims 1 to 15, wherein R4 is methyl.

20. A compound according to any one of the preceding claims, wherein R5 is H.

21. A compound according to any one of the preceding claims, wherein L1 is CO.

22. A compound according to any one of claims 1 to 20, wherein L1 is C(R3)2.

23. A compound according to any one of claims 1 to 20, wherein L1 is methylene.

24. A compound according to any one of the preceding claims, wherein L2 is CO.

25. A compound according to any one of claims 1 to 23, wherein L2 is C(R3)2.

26. A compound according to any one of claims 1 to 23, wherein L2 is methylene.

27. The compound according to any one of the preceding claims, wherein Ring A1 is a 3-7 membered cycloalkyl. The compound according to claim 27 , wherein Ring A1 is cyclohexyl.

29. The compound according to any one of claims 1 to 26, wherein Ring A1 is a 4-7 membered heterocycloalkyl group.

30. The compound according to claim 29, wherein Ring A1 is piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, azacyclohexanyl or azabicyclohexanyl. The compound according to claim 29 , wherein Ring A 1 is piperazinyl.

32. A compound according to any one of the preceding claims, wherein Ring A2 is a 3-7 membered cycloalkyl.

33. The compound according to claim 32, wherein Ring A2 is cyclohexyl.

34. The compound according to any one of claims 1 to 31, wherein Ring A2 is a 4-7 membered heterocycloalkyl.

35. The compound according to claim 34, wherein Ring A2 is piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, azacyclohexanyl or azabicyclohexanyl.

36. The compound according to claim 34, wherein Ring A2 is piperidinyl.

37. A compound according to any one of the preceding claims, wherein X1 is CH2.

38. A compound according to any one of claims 1 to 36, wherein X1 is CO.

39. A compound according to any one of the preceding claims, wherein X2 is CH2.

40. A compound according to any one of claims 1 to 38, wherein X2 is CO.

41. A compound according to any one of the preceding claims, which is a compound of formula II: or a pharmaceutically acceptable salt thereof; wherein Each R6 is independently H, D, C 1-6 Alkyl, C 3-6 Cycloalkyl or haloalkyl; p is 1, 2, 3, 4, 5, 6, 7 or 8; and Z is N or CR6.

42. The compound of claim 41, wherein Z is N.

43. The compound of claim 41, wherein p is 1.

44. The compound of claim 41, wherein p is 2.

45. The compound of claim 41, wherein p is 3.

46. ​​The compound of claim 41, wherein p is 4.

47. The compound of claim 41, wherein p is 5.

48. The compound of claim 41, wherein p is 6.

49. The compound of claim 41, wherein p is 7.

50. The compound of claim 41, wherein p is 8.

51. A compound according to any one of claims 41 to 50, wherein each R6 is H.

52. according to the compound described in any one of claims 41 to 50, wherein each R6 is C 1-6 alkyl.

53. A compound according to any one of claims 41 to 50, wherein each R6 is methyl.

54. A compound according to any one of the preceding claims 41 to 53, which is a compound of formula III: or a pharmaceutically acceptable salt thereof.

55. A compound according to any one of claims 41 to 54, which is a compound of formula IV: or a pharmaceutically acceptable salt thereof.

56. A compound according to any one of claims 41 to 55, which is a compound of formula V: or a pharmaceutically acceptable salt thereof.

57. A compound according to any one of claims 41 to 56, which is a compound of formula VI: or a pharmaceutically acceptable salt thereof.

58. The compound according to claim 1, which 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]pyridazine-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]pyridazine-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]pyridazine-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]pyridazine-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]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; 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]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-(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,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-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]pyridazine-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]pyridazine-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]pyridazine-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]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)-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-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]pyridazine-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]pyridazine-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]pyridazine-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]pyridazine-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]pyridazine-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]pyridazine-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]pyridazine-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]pyridazine-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]pyridazine-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]pyridazine-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]pyridazine-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]pyridazine-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-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)-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-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,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; 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-dimethylpiperazin-1-yl)methyl)morpholino)-1-oxoisoindolin-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-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]pyridazine-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]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-methyl-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; or a pharmaceutically acceptable salt thereof.

59. The compound according to claim 1, which 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]pyridazine-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]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,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]pyridazine-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]pyridazine-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]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-((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)-3,5-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]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-((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)-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]pyridazine-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]pyridazine-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]pyridazine-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]pyridazine-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]pyridazine-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]pyridazine-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]pyridazine-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]pyridazine-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]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-(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,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]pyridazine-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]pyridazine-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]pyridazine-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]pyridazine-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]pyridazine-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]pyridazine-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]pyridazine-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-(trifluoro-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; (3S)-3-(6-(4-((4-(2-(3-fluoro-2-hydroxyphenyl)-6a-(trifluoro-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; (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]pyridazine-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-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)-4-fluorocyclohexyl)methyl)piperazin-1-yl)-1-oxoisoindolin-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]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-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-fluoropiperidin-1-yl)methyl)piperidin-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]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-fluoro-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; (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]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]pyridazine-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-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)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]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-methyl-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-(((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)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]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]pyridazine-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.

60. A compound according to any one of the preceding claims in the form of a pharmaceutically acceptable salt.

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

62. A method of treating cancer in a subject in need thereof, comprising administering to the subject a compound according to any one of claims 1 to 60 or a pharmaceutical composition according to claim 61.

63. The method of claim 62, wherein the cancer is a SMARCA4-deficient cancer.

64. The method of claim 62 or claim 63, wherein the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer and stomach cancer; leukemia; benign and malignant lymphomas, in particular Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma (Kaposi's sarcoma), sarcoma, ... sarcoma), liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma and schwannoma; intestinal 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.

65. The method of any one of claims 62 to 64, wherein the cancer is T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-B ALL, pre-B lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, and Philadelphia chromosome-positive CML.

66. The method of claim 64, wherein the lung cancer is SMARCA4-deficient non-small cell lung cancer.

67. A method for degrading SMARCA4 protein, comprising contacting the SMARCA4 protein with a compound according to any one of claims 1 to 60 or a pharmaceutical composition according to claim 61.

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