BRM Targeted Compounds and Related Methods of Use

Abstract

The present disclosure is directed to compounds of formula (I). Pharmaceutical compositions containing the compounds of (I), as well as methods for their use and preparation, are also described. JPEG2025532611000445.jpg42129

Description

[Technical Field]

[0001] Provided herein are bifunctional compounds comprising a target protein-binding moiety and an E3 ubiquitin ligase-binding moiety, and related methods of use. The bifunctional compounds are useful as modulators of targeted ubiquitination, particularly with respect to switch / sucrose non-fermenting (SWI / SNF)-associated, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 2 (SMARCA2) (i.e., BRAHMA or BRM), which are degraded and / or otherwise inhibited by the bifunctional compounds disclosed herein. [Background technology]

[0002] The human switch / sucrose non-fermentable (SWI / SNF) complexes are ATP-dependent chromatin remodelers. These large complexes play important roles in essential cellular processes such as transcription, DNA repair, and replication by regulating DNA accessibility.

[0003] Mutations in genes encoding up to 20 canonical SWI / SNF subunits are observed in approximately 20% of all human cancers, with the highest mutation frequencies observed in rhabdoid tumors, female cancers (including ovarian, uterine, cervical, and endometrial), lung adenocarcinoma, gastric adenocarcinoma, melanoma, esophageal, and renal clear cell carcinoma.

[0004] SMARCA2 (BRM) and SMARCA4 (BRG1) are catalytic ATPase domain-containing subunits that are essential for SWI / SNF function in perturbing histone-DNA contacts, thereby providing access points for transcription factors and cognate DNA elements that facilitate gene activation and repression.

[0005] SMARCA2 and SMARCA4 share a high degree of homology (up to 75%). SMARCA4 is frequently mutated (i.e., deleted or inactivated) in primary tumors, particularly in lung cancer (12%), melanoma, liver cancer, and pancreatic cancer. SMARCA2 is one of the top essential genes in SMARCA4-mutated (deleted) cancer cell lines. This is because SMARCA4-deficient cancer cells exclusively depend on SMARCA2 ATPase activity for their chromatin remodeling activity for cellular functions such as cell proliferation, survival, and growth. Therefore, targeting SMARCA2 may be a promising therapeutic approach in SMARCA4-related or -deficient cancers (genetic synthetic lethality).

[0006] Previous studies have demonstrated strong synthetic lethality using gene expression manipulations such as RNAi. Downregulation of SMARCA2 gene expression in SMARCA4-mutant cancer cells results in suppression of cancer cell proliferation. However, SMARCA2 / 4 bromodomain inhibitors (e.g., PFI-3) show no or little effect on cell proliferation inhibition [Vangamudi et al. Cancer Res 2015]. This phenotypic discrepancy between gene expression downregulation and small molecule-based approaches led us to investigate proteolytic bispecific molecules in SMARCA4-deficient cancers.

[0007] SMARCA2 has also been reported to play a role in multiple myeloma expressing the t(4;14) chromosomal translocation [Chooi et al. Cancer Res abstract 2018]. SMARCA2 interacts with NSD2 and regulates the expression of genes such as PRL3 and CCND1. Downregulation of SMARCA2 gene expression by shRNA reduces the S phase of the cell cycle and suppresses cell proliferation in t(4;14) MM cells.

[0008] There is a need for therapeutic compounds that inhibit SMARCA2 and / or SMARCA4. Summary of the Invention

[0009] The present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: R1, Halo, C 1-6 alkyl, or haloalkyl; each R2 is independently H, D, or F; Each R3 is independently H, D, or C 1-6 Alkyl, haloalkyl, C 3-6 Heterocycloalkyl, or C 3-6 is cycloalkyl, n is 1, 2, or 3; m is 1, 2, 3, or 4; R4 is H, D, C 1-6 Alkyl, C 1-6 Alkoxyalkyl, C 3-6 Cycloalkyl, or C 1-6 is haloalkyl, R5 is H, D, or F; L1 is a bond, O, S, S(O), SO2, NR3, C(R3)2, or CO; L2 is a bond, O, S, S(O), SO2, NR3, C(R3)2, or CO; Ring A1 is a 6-membered aryl group or a 5- to 6-membered heteroaryl group, Ring A2 is a 3- to 7-membered cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, X1 is CH2, CO, CH=CH (when X2=CO), or N=CH (when X2=CO), X2 is CH2, CO, CH=CH (when X1=CO), or N=CH (when X1=CO), An alkyl group, a haloalkyl group, a cycloalkyl group, an alkoxyalkyl group, an aryl group, a heteroaryl group, or a heterocycloalkyl group is selected from one or more R f optionally substituted by a group, Each R fare independently selected from D, oxo, halogen, C1-C8 alkoxy, C1-C8 alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -OH, -CN, -NO, -C-C alkenyl, -C-C alkynyl, C 6-10 Aryl, C 5-12 Heteroaryl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Heterocycloalkyl, C 3-8 heterocycloalkenyl, -OR a , -SR a , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R b , -C(O)OR b , -C(O)NR c R d , -S(O)R b , -S(O)NR c R d , -S(O)(=NR b )R b , -SF5, -P(O)R b R b , -P(O)R c R d , -P(O)(OR b )(OR b ), -B(OR c )(OR d ), -S(O)R b , -C(O)NR b OR b , -S(O)2OR b , -OS(O)2OR b , or -OPO(OR b )(OR b ) wherein the C1-C8 alkyl is D, halogen, —OH, —CN, —OR a , -SR a , -NR a R d , or NR c R d and optionally substituted with 1 to 6 groups selected from Each R a However, independently, H, D, -C(O)R b , -C(O)OR c , -C(O)NR c R d , -C(=NR b )NR b R c 、 -C(=NOR b )NR b R c 、 -C(=NCN)NR b R c 、 -P(OR c )2, -P(O)R c R b , -P(O)R c R d , -P(O)OR c OR b , -S(O)R b , -S(O)NR c R d , -S(O)2R b , -S(O)NR c R d ,SiR b 3. -C1-C 10 Alkyl, -C2-C 10 Alkenyl, -C2-C 10 Alkynyl, C 6-10 Aryl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 5-12 Heteroaryl, C 3-8 Heterocycloalkyl, or C 3-8 heterocycloalkenyl, Each R b are independently H, D, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, C 6-10 Aryl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 5-12 Heteroaryl, C 3-8 Heterocycloalkyl, or C 3-8 heterocycloalkenyl, Each R cor R d However, independently, H, D, -C1-C 10 Alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O-C1-C6 alkyl, -O-cycloalkyl, C 6-10 Aryl, C 5-12 Heteroaryl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Heterocycloalkyl, or C 3-8 heterocycloalkenyl, or Or R c and R d is taken together with the atom to which they are both attached to form a monocyclic or polycyclic heterocycloalkyl, or a monocyclic or polycyclic heterocycloalkenyl group, or a pharmaceutically acceptable salt thereof.

[0010] Stereoisomers of the compounds of Formula I, as well as pharmaceutical salts and stereoisomers thereof, are also contemplated, described and encompassed herein. Methods of using the compounds of Formula I, and pharmaceutical compositions containing the compounds of Formula I, are described. DETAILED DESCRIPTION OF THE INVENTION

[0011] 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 terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure.

[0012] 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 limit of that range, and any other stated or intervening value within that stated range, is included in the disclosure unless the context clearly dictates otherwise (such as in the case of a group including the number of carbon atoms where each number of carbon atoms falling within the range is provided). The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where a stated range includes one or both of the upper or lower limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0013] The following terms are used to describe this disclosure. If a term is not specifically defined herein, the term will be given its art-recognized meaning by one of ordinary skill in the art applying the term in context to its use in describing this disclosure.

[0014] As used in this specification and the appended 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, unless the context clearly indicates otherwise. By way of example, "an element" means one element or more than one element.

[0015] The terms "co-administration" and "co-administering" or "combination therapy" refer to both simultaneous administration (administration of two or more therapeutic agents at the same time) and time-staggered administration (administration of one or more therapeutic agents at a different time than the administration of the additional therapeutic agent), so long as the therapeutic agents are present in the patient at some level, preferably in effective amounts, at the same time. In certain preferred embodiments, one or more of the compounds of the invention described herein are co-administered in combination with at least one additional bioactive agent, including, in particular, an anti-cancer agent. In particularly preferred embodiments, co-administration of the compounds results in synergistic activity and / or therapy, including anti-cancer activity.

[0016] As used herein, the term "compound," unless otherwise indicated, refers to any specific chemical compound disclosed herein and includes in context tautomers, positional isomers, geometric isomers, and, where applicable, stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers), thereof, as well as pharmaceutically acceptable salts and derivatives, including prodrugs and / or deuterated forms thereof, where applicable. Contemplated deuterated small molecules are those in which one or more hydrogen atoms contained in a drug molecule have been replaced by deuterium.

[0017] Within its use in 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), as well as specific enantiomers or enantiomerically enriched mixtures of the disclosed compounds. The term also refers to prodrug forms of compounds that have been modified to facilitate administration and delivery of the compound to the active site. In describing the compounds of the present invention, it should be noted that, among other things, numerous substituents and variables associated therewith are described. It will be understood by those skilled in the art that the molecules described herein are stable compounds as generally described below.

[0018] The term "ubiquitin ligase" refers to a family of proteins that promote the transfer of ubiquitin to specific substrate proteins and target the substrate proteins for degradation. For example, E3 ubiquitin ligase proteins, alone or in combination with E2 ubiquitin-conjugating enzymes, cause the attachment of ubiquitin to lysines on target proteins, subsequently targeting specific protein substrates for degradation by the proteasome. Thus, E3 ubiquitin ligases alone or in complex with E2 ubiquitin-conjugating enzymes are involved in the transfer of ubiquitin to target proteins. Generally, ubiquitin ligases are involved in polyubiquitination, in which a second ubiquitin is attached to the first, a third ubiquitin is attached to the second, and so on. Polyubiquitination targets proteins for degradation by the proteasome. However, some ubiquitination events are limited to monoubiquitination, in which only a single ubiquitin is added to a substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation, but instead may alter their cellular location or function, for example, by binding to other proteins with domains capable of binding to ubiquitin. Further complicating the issue, different lysines on ubiquitin can be targeted by E3s to create chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to create polyubiquitin, which is recognized by the proteasome.

[0019] As used herein, "cereblon (CRBN) E3 ubiquitin ligase" refers to the substrate recognition subunit of the Cullin-RING E3 ubiquitin ligase complex. CRBN is one of the most common E3 ligases recruited by bifunctional proteolytic targeting chimeras (PROTACs) to induce ubiquitination of target proteins and subsequent proteasomal degradation (Maniaci C. et al., Bioorg Med Chem. 2019, 27(12):2466-2479).

[0020] As used herein, the term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical having up to 12 carbon atoms. In some embodiments, the number of carbon atoms is specified (i.e., C 1- (C8 means 1 to 8 carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Alkyl groups may be optionally substituted as provided herein. In some embodiments, an alkyl group is C 1- C alkyl, and in some embodiments, it is C 1- It is a C4 alkyl.

[0021] When ranges of carbon atoms are used herein, such as C1-C6, all ranges as well as individual numbers of carbon atoms are included. For example, "C1-C3" includes C 1- C3, C 1- C2, C 2- C3, C1, C2, and C3.

[0022] When used in combination with a substituent defined herein, the term "optionally substituted" means that one or more hydrogens of the substituent may, but need not, be replaced with one or more suitable functional groups or other substituents provided herein. For example, the substituent may be halo, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo(C 1-6 ) Alkyl, C 1-6 Alkoxy, Halo(C 1-6 Alkoxy), C 1-6 Alkylthio, C 1-6 Alkylamino, NH2, NH(C 1-6 alkyl), N(C 1-6 alkyl)2, NH(C 1-6 Alkoxy), N(C 1-6Alkoxy)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)C 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 It may be optionally substituted with one or more alkyl, oxo, 6- to 12-membered aryl, benzyl, pyridinyl, pyrazolyl, thiazolyl, isothiazolyl, or other 5- to 12-membered heteroaryl groups. In some embodiments, each of the above optional substituents may itself be optionally substituted with one or two groups.

[0023] The term "optionally substituted -CH-" refers to "-CH-" or substituted -CH-. The substituted -CH- may also be referred to as -CH(substituent)- or -C(substituent)(substituent)-, where each substituent is independently selected from the optional substituents described herein.

[0024] The term "cycloalkyl," as used herein, refers to a 3- to 12-membered cyclic alkyl, including bridged and spiro rings (e.g., adamantine). Cycloalkyl groups can be fully saturated or partially unsaturated. The term "cycloalkyl" also includes polycondensed ring systems (e.g., ring systems containing 2, 3, or 4 rings), in which a single cycloalkyl ring (as defined above) can be fused with one or more groups selected from heterocycle, carbocycle, aryl, or heteroaryl to form a polycondensed ring system. Such polycondensed ring systems can be optionally substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocycle or heterocycle portion of the polycondensed ring. The rings of a polycondensed ring system can be connected to each other via fused, spiro, and bridged bonds, where permitted by valence requirements. It is understood that the individual rings of a polycondensed ring system can be connected to each other in any order. It is also understood that the point of attachment of multiple fused ring systems (as defined above for cycloalkyl) can be at any position on the cycloalkyl ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclohexyl, cycloheptyl, cyclooctyl, indenyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[4.1.0]heptanyl, spiro[3.3]heptanyl, and spiro[3.4]octanyl. In some embodiments, the cycloalkyl group is a 3- to 7-membered cycloalkyl.

[0025] The term "cycloalkenyl" when used alone or as part of a substituent group means an alkyl group having 3 to 10 carbon atoms ("C3-C 10"), preferably 3 to 6 carbon atoms ("C3-C6"). Cycloalkenyl groups of the present disclosure include monocyclic and polycyclic groups, such as bicyclic and tricyclic groups. In those embodiments having at least one polycyclic cycloalkenyl group, the cyclic groups can share one common atom (i.e., spirocyclic). In other embodiments having at least one polycyclic cycloalkenyl group, the cyclic groups share two common atoms (e.g., fused or bridged). The term -C3-C6 cycloalkenyl refers to a cycloalkenyl group having 3 to 6 carbon atoms. The cycloalkenyl group may be attached at any carbon atom of the partially saturated ring that results in a stable structure. Cycloalkenyl groups include groups in which a partially saturated ring is fused to an aryl group. Examples of cycloalkenyl groups include, for example, cyclopropenyl (C3), cyclobutenyl (C4), cyclopropenylmethyl (C4), cyclopentenyl (C5), cyclohexenyl (C6), 1-methylcyclopropenyl (C4), 2-methylcyclopentenyl (C4), adamantenyl (C 10 ), spiro[3.3]heptenyl, bicyclo[3.3.0]octenyl, indanyl, and the like. In some embodiments, the cycloalkenyl groups of the present disclosure are optionally substituted. Unless otherwise specified, in embodiments in which the cycloalkenyl group is substituted, the cycloalkenyl group can be substituted with 1, 2, or 3 substituents independently selected from: —OH, —CN, amino, halo, C-C alkyl, C-C alkoxy, C-C haloalkyl, and C-C haloalkoxy, —C(O)NH(C-C alkyl), —C(O)N(C-C alkyl), —OC(O)NH(C-C alkyl), —OC(O)N(C-C alkyl), —S(O)NH(C-C alkyl), and —S(O)N(C-C alkyl). In other embodiments, the cycloalkenyl group is selected from the group consisting of D, halogen, —OH, —CN, —OR a , -SR a , -NR a R d , or NR c R dor the cycloalkenyl group is optionally substituted with 1 to 6 groups selected from one or more R f is optionally substituted by a group.

[0026] As used herein, the term "alkenyl" refers to a C alkyl group containing at least one carbon-carbon double bond. 2- C 12 In some embodiments, an alkenyl group is optionally substituted. In some embodiments, an alkenyl group is a C 2- It is a C6 alkenyl.

[0027] As used herein, the term "acynyl" refers to a C alkyl group containing at least one carbon-carbon triple bond. 2- C 12 In some embodiments, an alkenyl group is optionally substituted. In some embodiments, an alkynyl group is a C 2- It is a C6 alkynyl.

[0028] The terms "alkoxy," "alkylamino," and "alkylthio" are used in their conventional sense to refer to an alkyl group attached to the remainder of the molecule via an oxygen atom ("oxy"), an amino group ("amino"), or a thio group. The term "alkylamino" includes mono- and di-alkylamino groups, where the alkyl portions may be the same or different.

[0029] As used herein, the term "alkoxyalkyl" refers to a linear monovalent hydrocarbon radical of one to six carbon atoms, as defined above, or a branched monovalent hydrocarbon radical of three to six carbon atoms substituted with an alkoxy group, e.g., 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.

[0030] The terms "halo" or "halogen," by themselves or as part of another substituent, mean a fluorine, chlorine, bromine, or iodine atom.

[0031] As used herein, the term "haloalkyl" refers to any alkyl radical having one or more hydrogen atoms replaced by halogen atoms.

[0032] The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms are replaced by a heteroatom selected from S, O, P, and N. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, alkyl amides, alkyl sulfides, and the like. The group may be a terminal group or a bridging group. As used herein, reference to a straight chain when used in the context of a bridging group refers to a direct chain of atoms connecting the two terminal positions of the bridging group.

[0033] As used herein, the term "aryl" refers to a monocyclic all-carbon aromatic ring or a polycondensed all-carbon ring system in which at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 6 to 12 carbon atoms. Aryl includes the phenyl radical. Aryl also includes polycondensed ring systems (e.g., ring systems containing 2, 3, or 4 rings) having about 9 to 12 carbon atoms in which at least one ring is aromatic and the other rings may or may not be aromatic. Such polycondensed ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbocyclic moiety of the polycondensed ring system. The rings of a polycondensed ring system can be connected to each other via fused, spiro, and bridged bonds, where permitted by valence requirements. It should be understood that the point of attachment of a polycondensed ring system, as defined above, can be at any position on the aromatic ring. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphth-yl, and the like.

[0034] The term "heteroaryl," as used herein, refers to a single aromatic ring having at least one atom other than carbon in the ring, the atom being selected from the group consisting of oxygen, nitrogen, and sulfur. "Heteroaryl" also includes multiple condensed ring systems having at least one such aromatic ring, which are further described below. Thus, "heteroaryl" includes a single aromatic ring of about 1 to 6 carbon atoms and 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 the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. "Heteroaryl" also includes polycondensed ring systems (e.g., ring systems containing 2, 3, or 4 rings), where a heteroaryl group, as defined above, is fused to one or more rings selected from heteroaryl (e.g., to form naphthyridinyl, such as 1,8-naphthyridinyl), heterocycle (e.g., to form 1,2,3,4-tetrahydronaphthyridinyl, such as 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (e.g., to form 5,6,7,8-tetrahydroquinolyl), and aryl (e.g., to form indazolyl) to form a polycondensed ring system. Thus, a heteroaryl (single aromatic ring or polycondensed ring system) has about 1 to 20 carbon atoms and about 1 to 6 heteroatoms in the heteroaryl ring. A heteroaryl (single aromatic ring or polycondensed ring system) can also have about 5 to 12 members or about 5 to 10 members in the heteroaryl ring. Polyfused ring systems may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic portions of the fused rings. The rings of a polyfused ring system may be connected to each other via fused, spiro, and bridged bonds, where permitted by valence requirements. It is understood that the individual rings of a polyfused ring system may be connected to each other in any order. It is also understood that the point of attachment of a polyfused ring system (as defined above for heteroaryl) may be at any position on the heteroaryl ring. It is also understood that the point of attachment of a heteroaryl or heteroaryl polyfused ring system may be at any suitable atom of the heteroaryl ring, including carbon atoms and heteroatoms (e.g., nitrogen).Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinylbenzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole, and 3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole. In one embodiment, the term "heteroaryl" refers to a single aromatic ring containing at least one heteroatom. For example, the term includes 5- and 6-membered monocyclic aromatic rings containing one or more heteroatoms. Non-limiting examples of heteroaryls include, but are not limited to, pyridyl, furyl, thiazole, pyrimidine, oxazole, and thiadiazole.

[0035] The term "heterocycloalkyl," when used alone or as part of a substituent, refers to any 3- to 12-membered monocyclic or polycyclic, saturated ring structure containing at least one heteroatom selected from the group consisting of O, N, P, B, and S. Heterocycloalkyl groups of the present disclosure include monocyclic groups and polycyclic groups, such as bicyclic and tricyclic groups. In those embodiments having at least one polycyclic heterocycloalkyl group, the cyclic groups can share one common atom (i.e., spirocyclic). In other embodiments having at least one polycyclic heterocycloalkyl group, the cyclic groups share two common atoms (e.g., fused or bridged). The term -C3-C6 heterocycloalkyl refers to a heterocycloalkyl group having 3 to 6 carbon ring atoms. The heterocycloalkyl group may be attached at any heteroatom or carbon atom of the group that results in a stable structure. Examples of heterocycloalkyl groups include azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, azepanyl, diazepanyl, oxepanyl, dioxepanyl, azocanyl, diazocanyl, oxocanyl, dioxocanyl, azaspiro[2.2]pentanyl, oxaazaspiro[3.3]heptanyl, oxaspiro[3.3]heptanyl, dioxaspiro[3.3]heptanyl, 3-azabicyclo[3.1.0]hexanyl, [ka] and the like. In some embodiments, the heterocycloalkyl groups of the present disclosure are optionally substituted. Unless otherwise specified, in embodiments in which the heterocycloalkyl group is substituted, the heterocycloalkyl group can be substituted with one, two, or three substituents independently selected from -OH, -CN, amino, halo, C-C alkyl, C-C alkoxy, C-C haloalkyl, and C-C haloalkoxy, -C(O)NH(C-C alkyl), -C(O)N(C-C alkyl), -OC(O)NH(C-C alkyl), -OC(O)N(C-C alkyl), -S(O)NH(C-C alkyl), and -S(O)N(C-C alkyl). In other embodiments, the heterocycloalkyl group can be substituted with D, halogen, -OH, -CN, -OR. a , -SR a , -NR a R d , or NR c R d or the heterocycloalkyl group is optionally substituted with 1 to 6 groups selected from one or more R f is optionally substituted by a group.

[0036] The term "heterocycloalkenyl," when used alone or as part of a substituent, refers to any 3- to 12-membered monocyclic or polycyclic, partially saturated ring structure containing at least one heteroatom selected from the group consisting of O, N, P, B, and S. Heterocycloalkenyl groups of the present disclosure include monocyclic groups and polycyclic groups, such as bicyclic and tricyclic groups. In those embodiments having at least one polycyclic heterocycloalkenyl group, the cyclic groups can share one common atom (i.e., spirocyclic). In other embodiments having at least one polycyclic heterocycloalkenyl group, the cyclic groups share two common atoms (e.g., fused or bridged). The term -C3-C6 heterocycloalkenyl refers to a heterocycloalkenyl group having 3 to 6 carbon atoms. The heterocycloalkenyl group may be attached at any heteroatom or carbon atom of the partially saturated ring that results in a stable structure. Heterocycloalkenyl groups include those in which the partially saturated ring is a ring such as, for example, isoindoline, [ka] or a partially saturated ring is fused to an aryl group such as, for example, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, [ka] and groups fused to a heteroaryl group such as. In some embodiments, the heterocycloalkenyl groups of the present disclosure are optionally substituted. Unless otherwise specified, in embodiments in which the heterocycloalkenyl group is substituted, the heterocycloalkenyl group can be substituted with one, two, or three substituents independently selected from -OH, -CN, amino, halo, C-C alkyl, C-C alkoxy, C-C haloalkyl, and C-C haloalkoxy, -C(O)NH(C-C alkyl), -C(O)N(C-C alkyl), -OC(O)NH(C-C alkyl), -OC(O)N(C-C alkyl), -S(O)NH(C-C alkyl), and -S(O)N(C-C alkyl). In other embodiments, the heterocycloalkenyl group can be substituted with D, halogen, -OH, -CN, -OR. a , -SR a , -NR a R d , or NR c R d or the heterocycloalkenyl group is optionally substituted with 1 to 6 groups selected from one or more R f is optionally substituted by a group.

[0037] As used herein, "one or more R f The term "group" refers to 1, 2, 3, 4, 5, 6, 7, or 8 R f In some embodiments, "one or more R f A "group" is one R f In some embodiments, "one or more R f A "group" is a group consisting of up to two R f In some embodiments, "one or more R f A "group" is a group consisting of up to three R f In some embodiments, "one or more R f A "group" is a group consisting of up to four R f In some embodiments, "one or more R f A "group" is a group consisting of up to five Rf In some embodiments, "one or more R f A "group" is a group consisting of up to six R f In some embodiments, "one or more R f A "group" is a group consisting of up to seven R f In some embodiments, "one or more R f A "group" is a group consisting of up to eight R f It is meant to include the group.

[0038] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), boron (B), and silicon (Si). Nitrogen and sulfur may be in the oxidized form, where feasible.

[0039] As used herein, the term "chiral" refers to molecules that have the property of not being superimposable on their mirror image partners, and the term "achiral" refers to molecules that are superimposable on their mirror image partners.

[0040] As used herein, the term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space, e.g., enantiomers, diastereomers, tautomers.

[0041] The terms "patient" or "subject" are used throughout this specification to describe an animal, preferably a human or livestock, to which 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 livestock such as horses, cows, sheep, etc. Generally, in this disclosure, the term patient refers to a human patient, unless otherwise stated or implied from the context of the use of the term.

[0042] The term "effective," when used within the context of its intended use, is used to describe the amount of a compound, composition, or ingredient that produces an intended result. The term effective encompasses all other effective amount or effective concentration terms otherwise described or used in this application.

[0043] "Pharmaceutically acceptable" means approved or approvable by a regulatory authority of the federal or state government or a corresponding authority in a country other than the United States, or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeias for use in animals, e.g., humans.

[0044] "Pharmaceutically acceptable salts" refers to salts of compounds of the present disclosure that are pharmaceutically acceptable and that possess the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may include inorganic or organic acid addition salts and base addition salts. Specific examples of such salts include the following: (1) salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or 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-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or coordinates with an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and, if the compound contains a basic functional group, salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc.

[0045] A "pharmaceutically acceptable excipient" refers to a substance that is non-toxic, biologically acceptable, and otherwise biologically suitable for administration to a subject, such as an inert substance that is added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a drug and is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0046] "Solvate" refers to a physical association of a compound of Formula I with one or more solvent molecules.

[0047] "Treating" or "treatment" of any disease or disorder, in one embodiment, refers to ameliorating the disease or disorder (e.g., preventing or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to improving at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, "treating" or "treatment" refers to delaying the onset of the disease or disorder.

[0048] In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: R1, Halo, C 1-6 Alkyl, or C 1-6 is haloalkyl, each R2 is independently H, D, or F; Each R3 is independently H, D, or C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Heterocycloalkyl, or C 3-6is cycloalkyl, n is 1, 2, or 3; m is 1, 2, 3, or 4; R4 is H, D, C 1-6 Alkyl, C 1-6 Alkoxyalkyl, C 3-6 Cycloalkyl, or C 1-6 is haloalkyl, R5 is H, D, or F; L1 is a bond, O, S, S(O), SO2, NR3, C(R3)2, or CO; L2 is a bond, O, S, S(O), SO2, NR3, C(R3)2, or CO; Ring A1 is a 6-membered aryl group or a 5- to 6-membered heteroaryl group, Ring A2 is a 3- to 7-membered cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, X1 is CH2, CO, CH=CH (when X2=CO), or N=CH (when X2=CO), X2 is CH2, CO, CH=CH (when X1=CO), or N=CH (when X1=CO), An alkyl group, a haloalkyl group, a cycloalkyl group, an alkoxyalkyl group, an aryl group, a heteroaryl group, or a heterocycloalkyl group is selected from one or more R f optionally substituted by a group, Each R f are independently selected from D, oxo, halogen, C1-C8 alkoxy, C1-C8 alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -OH, -CN, -NO, -C-C alkenyl, -C-C alkynyl, C 6-10 Aryl, C 5-12 Heteroaryl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Heterocycloalkyl, C 3-8 heterocycloalkenyl, -OR a , -SR a , -NR c R d , -NRa R c , -C(O)R b , -OC(O)R b , -C(O)OR b , -C(O)NR c R d , -S(O)R b , -S(O)NR c R d , -S(O)(=NR b )R b , -SF5, -P(O)R b R b , -P(O)R c R d , -P(O)(OR b )(OR b ), -B(OR c )(OR d ), -S(O)R b , -C(O)NR b OR b , -S(O)2OR b , -OS(O)2OR b , or -OPO(OR b )(OR b ) wherein the C1-C8 alkyl is D, halogen, —OH, —CN, —OR a , -SR a , -NR a R d , or NR c R d and optionally substituted with 1 to 6 groups selected from Each R a However, independently, H, D, -C(O)R b , -C(O)OR c , -C(O)NR c R d , -C(=NR b )NR b R c 、 -C(=NOR b )NR b R c 、 -C(=NCN)NR b R c 、 -P(OR c )2, -P(O)R c Rb , -P(O)R c R d , -P(O)OR c OR b , -S(O)R b , -S(O)NR c R d , -S(O)2R b ,-S(O)2NR c R d , SiR b 3. -C1-C 10 Alkyl, -C2-C 10 Alkenyl, -C2-C 10 Alkynyl, C 6-10 Aryl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 5-12 Heteroaryl, C 3-8 Heterocycloalkyl, or C 3-8 heterocycloalkenyl, Each R b are independently H, D, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, C 6-10 Aryl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 5-12 Heteroaryl, C 3-8 Heterocycloalkyl, or C 3-8 heterocycloalkenyl, Each R c or R d However, independently, H, D, -C1-C 10 Alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O-C1-C6 alkyl, -O-cycloalkyl, C 6-10 Aryl, C 5-12 Heteroaryl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Heterocycloalkyl, or C 3-8 heterocycloalkenyl, or Or R c and R dis taken together with the atom to which they are both attached to form a monocyclic or polycyclic heterocycloalkyl, or a monocyclic or polycyclic heterocycloalkenyl group, or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, R of Formula I 1 Ha, Halo, C 1-6 Alkyl, or C 1-6 In some embodiments, R of Formula I is haloalkyl. 1 In some embodiments, R of formula I is halo. 1 is C 1-6 In some embodiments, R of formula I is alkyl. 1 is C 1-6 It is haloalkyl.

[0050] In other embodiments, R of Formula I 1 is F. In other embodiments, R of Formula I 1 In another embodiment, R of Formula I is Cl. 1 is methyl.

[0051] In some embodiments, each R2 of formula I is independently H, D, or F. In some embodiments, each R2 of formula I is H. In some embodiments, each R2 of formula I is D. In some embodiments, each R2 of formula I is F.

[0052] In other embodiments, at least one R2 of formula I is H. In other embodiments, at least one R2 of formula I is D. In other embodiments, at least one R2 of formula I is F.

[0053] 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.

[0054] In some embodiments, each R of formula I is independently selected from H, D, C1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Heterocycloalkyl, or C 3-6 In some embodiments, each R of formula I is H. In some embodiments, each R of formula I is D. In some embodiments, each R of formula I is C 1-6 In some embodiments, each R of formula I is C 1-6 In some embodiments, each R of formula I is C 3-6 In some embodiments, each R of formula I is C 3-6 It is cycloalkyl.

[0055] In other embodiments, at least one R3 of formula I is H. In other embodiments, at least one R3 of formula I is D. In other embodiments, at least one R3 of formula I is C 1-6 In another embodiment, at least one R of Formula I is haloalkyl. In another embodiment, at least one R of Formula I is C 3-6 It is cycloalkyl.

[0056] In some embodiments, m in Formula (I) is 1, 2, 3, or 4. 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.

[0057] In some embodiments, R of formula I is independently H, D, C 1-6 Alkyl, C 1-6 Alkoxyalkyl, haloalkyl, or C 3-6 In some embodiments, R4 of formula I is H. In some embodiments, R4 of formula I is D. In other embodiments, R4 of formula I is C 1-6 In other embodiments, R4 of formula I is C 1-6 In other embodiments, R4 of formula I is C1-6 In yet another embodiment, R4 of formula I is C 3-6 It is cycloalkyl.

[0058] In some embodiments, R5 of formula I is independently H, D, or F. In some embodiments, R5 of formula I is H. In other embodiments, R5 of formula I is D. In other embodiments, R5 of formula I is F.

[0059] In some embodiments, L1 in Formula (I) is a bond, O, S, S(O), SO2, NR3, C(R3)2, or CO. In some embodiments, L1 in Formula (I) is a bond. In some embodiments, L1 in Formula (I) is O. In some embodiments, L1 in Formula (I) is S. In other embodiments, L1 in Formula (I) is S(O). In other embodiments, L1 in Formula (I) is SO2. In other embodiments, L1 in Formula (I) is NR3. In still other embodiments, L1 in Formula (I) is C(R3)2. In still other embodiments, L1 in Formula (I) is CO. In still other embodiments, L1 in Formula (I) is methylene.

[0060] In some embodiments, L2 in Formula I is a bond, O, S, S(O), SO2, NR3, C(R3)2, or CO. In some embodiments, L2 in Formula (I) is a bond. In some embodiments, L2 in Formula (I) is O. In some embodiments, L2 in Formula (I) is S. In other embodiments, L2 in Formula (I) is S(O). In other embodiments, L2 in Formula (I) is SO2. In other embodiments, L2 in Formula (I) is NR3. In still other embodiments, L2 in Formula (I) is C(R3)2. In still other embodiments, L2 in Formula (I) is CO. In still other embodiments, L2 in Formula (I) is methylene.

[0061] In some embodiments, ring A1 of Formula (I) is a 6-membered aryl group or a 5- to 6-membered heteroaryl group. In some embodiments, ring A1 of Formula (I) is a 6-membered aryl group. In some embodiments, ring A1 of Formula (I) is a phenyl group. In other embodiments, ring A1 is a 5- to 6-membered heteroaryl group. In other embodiments, ring A1 is a pyridine group. In other embodiments, ring A1 is a pyrimidine group.

[0062] In some embodiments, ring A2 of Formula (I) is a 3- to 7-membered cycloalkyl group or a 4- to 7-membered heterocycloalkyl group. In some embodiments, ring A2 of Formula (I) is a 3- to 7-membered cycloalkyl group. In some embodiments, ring A2 of Formula (I) is a cyclohexyl group. In some embodiments, ring A2 is a 4- to 7-membered heterocycloalkyl group. In some embodiments, ring A2 of Formula (I) is a piperazine group, a morpholine group, a piperidine group, a pyrrolidine group, an azetidine group, or an azabicyclohexane group.

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

[0064] In some embodiments, X1 in Formula (I) is CH2, CO, CH=CH (when X2=CO), or N=CH (when X2=CO). 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).

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

[0066] In some embodiments, each R of formula I f are independently selected from D, oxo, halogen, C1-C8 alkoxy, C1-C8 alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -OH, -CN, -NO, -C-C alkenyl, -C-C alkynyl, C 6-10 Aryl, C 5-12 Heteroaryl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Heterocycloalkyl, C 3-8 heterocycloalkenyl, -OR a , -SR a , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R b , -C(O)OR b , -C(O)NR c R d , -S(O)R b , -S(O)NR c R d , -S(O)(=NR b )R b , -SF5, -P(O)R b R b , -P(O)R c R d , -P(O)(OR b )(OR b ), -B(OR c )(OR d ), -S(O)R b , -C(O)NR b OR b, -S(O)2OR b , -OS(O)2OR b , or -OPO(OR b )(OR b ) wherein the C1-C8 alkyl is D, halogen, —OH, —CN, —OR a , -SR a , -NR a R d , or NR c R d is optionally substituted with 1 to 6 groups selected from

[0067] In some embodiments, at least one R of formula I f is D. In some embodiments, at least one R of formula I f In some embodiments, at least one R of formula I is oxo. f is halogen. In some embodiments, at least one R of formula I f is C1-C8 alkoxy. In some embodiments, at least one R of formula I f is C1-C8 alkyl. In some embodiments, C1-C8 alkyl is selected from D, halogen, —OH, —CN, —OR a , -SR a , -NR a R d , or NR c R d In some embodiments, at least one R of Formula I is optionally substituted with 1 to 6 groups selected from f In some embodiments, at least one R of formula I is haloalkyl. f In some embodiments, R of formula I is —OH. f In some embodiments, at least one R of formula I is -CN. f In some embodiments, at least one R of formula I is -NO. f is —C2-C6 alkenyl. In some embodiments, at least one R of formula I f is -C2-C6 alkynyl. In some embodiments, at least one R of formula I is -C2-C6 alkynyl.f is C 6-10 In some embodiments, at least one R of formula I is aryl. f is C 5-12 In some embodiments, at least one R of formula I is heteroaryl. f is C 3-8 In other embodiments, at least one R of formula I is cycloalkyl. f is C 3-8 In other embodiments, at least one R of formula I is cycloalkenyl. f is C 3-8 In other embodiments, at least one R of formula I is heterocycloalkyl. f is C 3-8 In other embodiments, at least one R of formula I is heterocycloalkenyl. f -OR a In other embodiments, at least one R of formula I is f -SR a In other embodiments, at least one R of formula I is f is -NR c R d In other embodiments, at least one R of formula I is f is -NR a R c In other embodiments, at least one R of formula I is f is -C(O)R b In other embodiments, at least one R of formula I is f is -OC(O)R b In other embodiments, at least one R of formula I is f is -C(O)OR b In other embodiments, at least one R of formula I is f is -C(O)NR c R d In yet another embodiment, at least one R of formula I is f is -S(O)R b In yet another embodiment, at least one R of formula I is f is -S(O)NR c R dIn yet another embodiment, at least one R of formula I is f is -S(O)(=NR b )R b In yet another embodiment, at least one R of formula I is f In yet another embodiment, at least one R of formula I is -SF5. f is -P(O)R b R b In yet another embodiment, at least one R of formula I is f is -P(O)(OR b )(OR b In yet another embodiment, at least one R of formula I is f is -B(OR c )(OR d In yet another embodiment, at least one R of formula I is f is -S(O)2R b In yet another embodiment, at least one R of formula I is f is -C(O)NR b OR b In yet another embodiment, at least one R of formula I is f is -S(O)2OR b In yet another embodiment, at least one R of formula I is f is -OS(O)2OR b In yet another embodiment, at least one R of formula I is f is -OPO(OR b )(OR b )

[0068] In some embodiments, each R of formula I a are independently H, D, and -C(O)R b , -C(O)OR c , -C(O)NR c R d , -C(=NR b )NR b R c 、 -C(=NOR b )NR b R c 、 -C(=NCN)NRb R c 、 -P(OR c )2, -P(O)R c R b , -P(O)OR c OR b , -S(O)R b , -S(O)NR c R d , -S(O)2R b , -S(O)NR c R d , SiR b 3. -C1-C 10 Alkyl, -C2-C 10 Alkenyl, -C2-C 10 Alkynyl, C 6-10 Aryl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 5-12 Heteroaryl, C 3-8 Heterocycloalkyl, or C 3-8 It is heterocycloalkenyl.

[0069] In some embodiments, at least one R of formula I a is H. In some embodiments, at least one R of formula I a is D. In some embodiments, at least one R of formula I a Ha, ha, -C(O)R b In some embodiments, at least one R of formula I is a is -C(O)OR c In some embodiments, at least one R of formula I is a is -C(O)NR c R d In some embodiments, at least one R of formula I is a is -C(=NR b )NR b R c In some embodiments, at least one R of formula I is a is C(=NOR b )NR b R cIn some embodiments, at least one R of formula I is a is -C(=NCN)NR b R c is.

[0070] In other embodiments, at least one R of Formula I a is -P(OR c )2, -P(O)R c R b , -P(O)OR c OR b , -S(O)R b , -S(O)NR c R d , -S(O)2R b , -S(O)NR c R d , SiR b 3, etc. In still other embodiments, at least one R of Formula I a is -C1-C 10 Alkyl, -C2-C 10 Alkenyl, -C2-C 10 Alkynyl, C 6-10 Aryl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 5-12 Heteroaryl, C 3-8 Heterocycloalkyl, C 3-8 heterocycloalkenyl and the like.

[0071] In some embodiments, each R of formula I b are independently H, D, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, C 6-10 Aryl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 5-12 Heteroaryl, C 3-8 Heterocycloalkyl, or C 3-8 It is heterocycloalkenyl.

[0072] In some embodiments, at least one R of formula I b is H. In some embodiments, at least one R of formula Ib is D. In some embodiments, at least one R of formula I b is —C1-C6 alkyl. In some embodiments, at least one R of formula I b is —C2-C6 alkenyl. In some embodiments, at least one R of formula I b is —C2-C6 alkynyl. In other embodiments, at least one R of Formula I is —C2-C6 alkynyl. b is C 6-10 In other embodiments, at least one R of formula I is aryl. b is C 3-8 In other embodiments, at least one R of formula I is cycloalkyl. b is C 3-8 In other embodiments, at least one R of formula I is cycloalkenyl. b is C 5-12 In other embodiments, at least one R of formula I is heteroaryl. b is C 3-8 In other embodiments, at least one R of formula I is heterocycloalkyl. b is C 3-8 It is heterocycloalkenyl.

[0073] In some embodiments, each R of formula I c or R d are independently H, D, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, C 6-10 Aryl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 5-12 Heteroaryl, C 3-8 Heterocycloalkyl, or C 3-8 It is heterocycloalkenyl.

[0074] In some embodiments, R of Formula I c or R d is H. In some embodiments, R of formula I c or R d is D. In some embodiments, R of formula I c or Rd is -C1-C 10 In some embodiments, R of formula I is alkyl. c or R d is —C2-C6 alkenyl. In some embodiments, R of Formula I c or R d is -C2-C6 alkynyl. In another embodiment, R of Formula I c or R d is -OC1-C6 alkyl. In another embodiment, R of Formula I c or R d is —O-cycloalkyl. In another embodiment, R of Formula I c or R d is C 6-10 In another embodiment, R of Formula I is aryl. c or R d is C 3-8 In another embodiment, R of Formula I is cycloalkyl. c or R d is C 3-8 In another embodiment, R of Formula I is cycloalkenyl. c or R d is C 5-12 In another embodiment, R of Formula I is heteroaryl. c or R d is C 3-8 In another embodiment, R of Formula I is heterocycloalkyl. c or R d is C 3-8 It is heterocycloalkenyl.

[0075] In yet other embodiments, R of Formula I c and R d and R 2 , taken together with the atoms to which they are both attached, form a monocyclic or polycyclic heterocycloalkyl or monocyclic or polycyclic heterocycloalkenyl group. c and R d In yet another embodiment, R of Formula I forms a monocyclic heterocycloalkyl. c and R dIn yet another embodiment, R of Formula I forms a polycyclic heterocycloalkyl. c and R d forms a monocyclic heterocycloalkenyl group. In yet another embodiment, R of Formula I c and R d forms a polycyclic heterocycloalkenyl group.

[0076] 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.

[0077] In some embodiments, the compound of Formula (I) is a compound of Formula IIa and Formula IIb: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R4, L1, ring A1, L2, ring A2, X1, and X2 is represented by a compound of Formula IIa and Formula IIb, or a pharmaceutically acceptable salt thereof, as defined above with respect to Formula (I).

[0078] In some embodiments, the compound of Formula (I) is a compound of Formula IIIa and Formula IIIb: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R4, L1, L2, ring A2, X1, and X2 is defined above for formula (I); Represented by compounds of Formula IIIa and Formula IIIb, or a pharmaceutically acceptable salt thereof, wherein each Z is independently N or CR6, and R6 is the same as Rf.

[0079] In some embodiments of Formula IIIa or Formula IIIb, each R6 is independently H, D, halo, C 1-6 Alkyl, C 1-6Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, or C 3-6 It is cycloalkyl.

[0080] In some embodiments of Formula IIIa or Formula IIIb, each R6 is independently H, D, halo, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, or C 3-6 It is cycloalkyl.

[0081] In some embodiments, each Z in Formula IIIa or Formula IIIb is independently N or CR6. In some embodiments, each Z in Formula IIIa or Formula IIIb is N. In some embodiments, each Z in Formula IIIa or Formula IIIb is CR6. In other embodiments, at least one Z in Formula IIIa or Formula IIIb is N. In other embodiments, at least two Z in Formula IIIa or Formula IIIb are N. In other embodiments, at least one Z in Formula IIIa or Formula IIIb is CR6. In other embodiments, at least two Z in Formula IIIa or Formula IIIb are CR6.

[0082] In some embodiments, each R of Formula IIIa or Formula IIIb is independently H, D, halo, —CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, or C 3-6 In some embodiments, each R6 of Formula IIIa or Formula IIIb is H. In some embodiments, each R6 of Formula IIIa or Formula IIIb is D. In some embodiments, each R6 of Formula IIIa or Formula IIIb is halo. In some embodiments, each R6 of Formula IIIa or Formula IIIb is -CN. In other embodiments, each R6 of Formula IIIa or Formula IIIb is C 1-6 In other embodiments, each R6 in Formula IIIa or Formula IIIb is C 1-6In other embodiments, each R6 in Formula IIIa or Formula IIIb is C 1-6 In other embodiments, each R6 in Formula IIIa or Formula IIIb is C 1-6 In other embodiments, each R6 in Formula IIIa or Formula IIIb is C 3-6 It is cycloalkyl.

[0083] In another embodiment, at least one R6 of Formula IIIa or Formula IIIb is H. In another embodiment, at least one R6 of Formula IIIa or Formula IIIb is D. In another embodiment, at least one R6 of Formula IIIa or Formula IIIb is halo. In another embodiment, at least one R6 of Formula IIIa or Formula IIIb is -CN. In another embodiment, at least one R6 of Formula IIIa or Formula IIIb is C 1-6 In other embodiments, at least one R6 of Formula IIIa or Formula IIIb is C 1-6 In other embodiments, at least one R6 of Formula IIIa or Formula IIIb is C 3-6 It is cycloalkyl.

[0084] In some embodiments, the compound of Formula (I) is a compound of Formula IVa and Formula IVb [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R4, L1, L2, X1, and X2 is defined above for formula (I), each of Z and R6 is defined above for formula IIIa or formula IIIb, and Z1 is N or CR6, and the compounds are represented by compounds of formula IVa and formula IVb, or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, Z1 of formula IVa or formula IVb is N or CR6. In some embodiments, Z1 of formula IVa or formula IVb is N. In some embodiments, Z1 of formula IVa or formula IVb is CR6.

[0086] In some embodiments, the compound of Formula (I) is a compound of Formula Va and Formula Vb [ka] or a pharmaceutically acceptable salt thereof, wherein each R1, R2, R4, and L1 is defined above for Formula (I), each Z and R6 is defined above for Formula IIIa or Formula IIIb, and Z1 is defined above for Formula IVa or Formula IVb, or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments, the compound of Formula (I) is a compound of Formula VIa and Formula VIb [ka] or a pharmaceutically acceptable salt thereof, wherein each R1, R2, and R4 is defined above for Formula (I), each Z and R6 is defined above for Formula IIIa or Formula IIIb, and Z1 is defined above for Formula VIa or Formula VIb, or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments, the compound of Formula (I) is a compound of Formula VIIa and Formula VIIb [ka] or a pharmaceutically acceptable salt thereof, wherein each R2, R4, and L1 is defined above for Formula (I), each Z and R6 is defined above for Formula IIIa or Formula IIIb, and Z1 is defined above for Formula VIa or Formula VIb, or a pharmaceutically acceptable salt thereof.

[0089] In still further embodiments, the compound of formula (I) is 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)benzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-methylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(5-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-fluorobenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)benzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(3-chloro-4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)benzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-methylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3-chloro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)benzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2,5-dimethylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3-chloro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-methylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-methylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-methoxybenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-fluorobenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-isopropylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-(trifluoromethyl)benzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-isopropylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2,6-dimethylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2,3-dimethylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3-chloro-5-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-methylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(2-hydroxy-3-methylphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-methylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3-chloro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-methoxybenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3-chloro-5-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)benzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(2-hydroxy-3-methylphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)benzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-(trifluoromethoxy)benzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(4-(((6aR,8R)-2-(3-chloro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)benzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((2-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)thio)pyrimidin-5-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((6-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((6-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((6-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((6-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((6-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((6-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((6-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[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-((6-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)(methyl)amino)pyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-methylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(1-(4-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-methylbenzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((6-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)thio)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or a pharmaceutically acceptable salt thereof.

[0090] In still further embodiments, the compound of formula (I) is 3-(6-(4-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylpyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((2-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4,6-dimethylpyrimidin-5-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((2-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyrimidin-5-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-ethylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-fluoro-4-methylpyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3,4-dimethylpyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((6-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-ethylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3,6-dimethylpyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((2-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-isopropylpyrimidin-5-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-methylpyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((6-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-methoxypyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((6-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-fluoropyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((6-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((6-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-methylpyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((6-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 5-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)methyl)-2-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylnicotinonitrile, 3-(6-(4-((6-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)thio)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((6-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-fluoro-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((6-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2,4-dimethylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((6-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylpyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((5-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylpyrazin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylpyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((6-ethyl-5-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((6-ethyl-5-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyrazin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-fluoro-6-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((5-fluoro-6-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-fluoro-6-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-exahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-fluoropyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(5-(4-((5-(((6aS,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-(trifluoromethyl)pyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(5-(4-((5-(((6aS,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-methylpyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((2-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4,6-dimethylpyrimidin-5-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 5-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)methyl)-2-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)isonicotinonitrile, (S)-3-(6-(1-((2-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyrimidin-5-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((2-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4,6-dimethylpyrimidin-5-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3,6-dimethylpyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-methylpyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-methylpyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((6-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-fluoropyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((5-chloro-6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4,5-dimethylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2,5-dimethylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(1-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-fluoropyridin-3-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((6-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-fluoro-4-methylpyridin-3-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylpyrazin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((6-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(2-hydroxy-3-methylphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((5-(((6aR,8R)-6a-ethyl-2-(2-hydroxy-3-methylphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3,4-dimethylpyridin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((2-(((6aS,8R)-6a-ethyl-2-(2-hydroxy-3-methylphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4,6-dimethylpyrimidin-5-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((5-(((6aS,8R)-6a-ethyl-2-(2-hydroxy-3-methylphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-methylpyridin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((3-chloro-5-(((6aS,8R)-2-(3-chloro-2-hydroxyphenyl)-6a-ethyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((6-(((6aR,8R)-2-(3-chloro-2-hydroxyphenyl)-6a-ethyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((5-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-fluoropyridin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((2-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4,6-dimethylpyrimidin-5-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((5-(((6aS,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyrazin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((5-(((6aS,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-methylpyridin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((2-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyrimidin-5-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(1-((6-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(1-((6-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or a pharmaceutically acceptable salt thereof.

[0091] It will be apparent that compounds of Formula I, including all subgenera described herein, may possess multiple stereocenters. As a result, multiple stereoisomers (enantiomers and diastereomers) of compounds of Formula I (and the subgenera described herein) exist. The present disclosure contemplates and includes each stereoisomer of any compound of Formula I (and the subgenera described herein) and mixtures of such stereoisomers.

[0092] Pharmaceutically acceptable salts and solvates of the compounds of Formula I (including all subgenera described herein) are also within the scope of this disclosure.

[0093] Isotopic variations of the compounds of Formula I (including all subgenera described herein) are also contemplated by the present disclosure.

[0094] Pharmaceutical compositions and methods of administration The pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof, as an active ingredient. If desired, the pharmaceutical composition contains a pharmaceutically acceptable salt and / or coordination complex thereof, as well as one or more pharmaceutically acceptable excipients, carriers including inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants.

[0095] The pharmaceutical composition can be administered alone or in combination with one or more other drugs, which are also typically administered in the form of a pharmaceutical composition.If desired, one or more compounds of the present invention and other drugs can be mixed in a preparation, or both components can be formulated in separate preparations and used separately or in combination at the same time.

[0096] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions of the present invention is 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.10%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.51%, 0.52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65 %, 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.

[0097] In some embodiments, the concentration of one or more compounds of the present invention is 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 15.75 ... 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%, or greater than 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number in a range defined by and including any two of the above numbers) w / w, w / v, or v / v.

[0098] In some embodiments, the concentration of one or more compounds of the present invention is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 24%, from about 0.08% to about 10%, from about 0.09% to about 12%, from about 0.10% to about 13%, from about 0.11% to about 14%, from about 0.12% to about 15%, from about 0.13% to about 16%, from about 0.14% to about 17%, from about 0.15% to about 18%, from about 0.16% to about 19%, from about 0.17% to about 20%, from about 0.18% to about 22%, from about 0.19% to about 23%, from about 0.19% to about 24%, from about 0.19% to about 25%, from about 0.19% to about 26%, from about 0.19% to about 27%, from about 0.19% to about 28%, from about 0.19% to about 29%, from about 0.19% to about 25%, from about 0.19% to about 26 ...7%, from about 0.19% to about 28%, from about % to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, or about 1% to about 10% w / w, w / v, or v / v.

[0099] In some embodiments, the concentration of one or more compounds of the present invention is within 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%, or about 0.1% to about 0.9% w / w, w / v, or v / v.

[0100] In some embodiments, the amount of one or more compounds of the present invention is 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 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 in a range defined by and including any two of the foregoing numbers).

[0101] In some embodiments, the amount of one or more compounds of the present invention is 0.0001g, 0.0002g, 0.0003g, 0.0004g, 0.0005g, 0.0006g, 0.0007g, 0.0008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.003g, 0.0035g, 0.004 ... g, 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, 0.095g, 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 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 a range defined by and including any two numbers above).

[0102] In some embodiments, the amount of one or more compounds of the present invention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

[0103] The compounds according to the present invention are effective over a wide dosage range. For example, in the treatment of adult humans, 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 may be used. An exemplary dosage is 10 to 30 mg per day. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject being treated, the body weight of the subject being treated, and the preference and experience of the attending physician.

[0104] Pharmaceutical compositions of the present invention typically comprise an 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, permeation enhancers, solubilizers, and adjuvants.

[0105] Non-limiting exemplary pharmaceutical compositions and methods for preparing them are described below.

[0106] Pharmaceutical composition for oral administration In some embodiments, the present invention provides a pharmaceutical composition for oral administration comprising a compound of the present invention and a pharmaceutical excipient suitable for oral administration.

[0107] In some embodiments, the present invention provides a solid pharmaceutical composition for oral administration containing (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 contains (iv) an effective amount of a third pharmaceutical agent.

[0108] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral ingestion. Pharmaceutical compositions of the present invention suitable for oral administration can be provided as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays, each containing a predetermined amount of the active ingredient as a powder or granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with a carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with a liquid carrier or finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired presentation. For example, tablets can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with excipients such as, but not limited to, binders, lubricants, inert diluents, and / or surfactants or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0109] Because water can accelerate the degradation of some compounds, the present invention also encompasses anhydrous pharmaceutical compositions and dosage forms containing active ingredients. For example, water can be added (e.g., 5%) in pharmaceutical applications as a means of simulating long-term storage to determine characteristics such as shelf life or the stability of a formulation over time. The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-moisture-containing ingredients and low-moisture or low-humidity conditions. Pharmaceutical compositions and dosage forms of the present invention containing lactose can be made anhydrous if substantial contact with moisture and / or humidity is expected during manufacturing, packaging, and / or storage. Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous nature. Thus, anhydrous compositions can be packaged using materials known to prevent exposure to water, allowing them to be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit-dose containers, blister packs, and strip packs.

[0110] The active ingredient can be combined in an intimate mixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. Carriers can take a variety of forms, depending on the preparation form desired for administration. In preparing compositions for oral dosage forms, any pharmaceutical medium can be used as a carrier, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., for oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols, or carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants, and in some embodiments, lactose can be used for oral solid preparations. For example, suitable carriers include powders, capsules, and tablets with solid oral preparations. If desired, tablets can be coated by standard aqueous or non-aqueous techniques.

[0111] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as gum acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

[0112] 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.

[0113] Disintegrants can be used in the compositions of the present invention to provide tablets that disintegrate when exposed to an aqueous environment. Using too much disintegrant can produce tablets that disintegrate in the bottle. Using too little can result in insufficient disintegration, which can alter the rate and extent of release of the active ingredient from the dosage form. Therefore, a dosage form of the compound disclosed herein can be formed using a sufficient amount of disintegrant that is neither too little nor too much to adversely alter the release of the active ingredient. The amount of disintegrant used can vary based on the type of formulation and mode of administration and can be readily discerned by those skilled in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, 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.

[0114] Lubricants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Additional lubricants include, for example, syloid silica gel, coagulated aerosol of synthetic silica, or mixtures thereof. Lubricants can optionally be added in an amount of less than about 1 weight percent of the pharmaceutical composition.

[0115] When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient therein may be combined with a diluent such as water, ethanol, propylene glycol, glycerin, and various combinations thereof, along with various sweetening or flavoring agents, coloring agents or dyes, and, if desired, emulsifying and / or suspending agents.

[0116] Tablets may be uncoated, or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate can be used. Formulations for oral use may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0117] 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, i.e., 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.

[0118] Suitable hydrophilic surfactants will generally have an HLB value of at least 10, while suitable lipophilic surfactants will 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 higher solubility in oil, while surfactants with higher HLB values ​​are more hydrophilic and have higher solubility in aqueous solutions.

[0119] Hydrophilic surfactants are generally considered to be compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is generally not applicable. Similarly, lipophilic (e.g., hydrophobic) surfactants are compounds having an HLB value of about 10 or less. However, the HLB value of a surfactant is only a rough guideline that is commonly used to enable the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0120] The hydrophilic surfactant may be either ionic or nonionic. Suitable ionic surfactants include alkylammonium salts, fusidate salts, fatty acid derivatives of amino acids, oligopeptides, and polypeptides, glyceride derivatives of amino acids, oligopeptides, and polypeptides, lecithin and hydrogenated lecithin, lysolecithin and hydrogenated lysolecithin, phospholipids and derivatives thereof, lysophospholipids and derivatives thereof, carnitine fatty acid ester salts, alkyl sulfate salts, fatty acid salts, docusate sodium, acyl lactylates, mono- and diacetylated tartaric acid esters of mono- and diglycerides, succinylated mono- and diglycerides, citrate esters of mono- and diglycerides, and mixtures thereof.

[0121] Among the aforementioned groups, ionic surfactants include, by way of example, lecithin, lysolecithin, phospholipids, lysophospholipids and their derivatives, carnitine fatty acid ester salts, salts of alkyl sulfates, fatty acid salts, docusate sodium, acyl lactylates, mono- and diacetylated tartaric acid esters of mono- and diglycerides, succinylated mono- and diglycerides, citrate esters of mono- and diglycerides, and mixtures thereof.

[0122] Ionic surfactants include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactic acid esters of fatty acids, stearoyl-2-lactate, stearoyl lactate, succinyl The ionic forms may be acetylated monoglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, citrate esters of mono / diglycerides, cholyl sarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teraceyl sulfate, docusate, lauroylcarnitine, palmitoylcarnitine, myristoylcarnitine, and salts and mixtures thereof.

[0123] Hydrophilic nonionic surfactants include, but are not limited to, alkyl glucosides, alkyl maltosides, alkyl thioglucosides, lauryl macrogol glycerides, 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 interesterification products of polyols and 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 interesterification products of polyols and at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a sugar.

[0124] Other hydrophilic nonionic surfactants include 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, PE G-20 Dilaurate, PEG-25 Glyceryl Trioleate, PEG-32 Dioleate, PEG-20 Glyceryl Laurate, PEG-30 Glyceryl Laurate, PEG-20 Glyceryl Stearate, PEG-20 Glyceryl Oleate, PEG-30 Glyceryl Oleate, PEG-30 Glyceryl Laurate, PEG-40 Glyceryl Laurate, PEG-40 Palm Kernel Oil, PEG-50 Hydrogenated Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil, PEG- 40 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Caprate / Caprylate Glyceride, PEG-8 Caprate / Caprylate Glyceride, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Phytosterol, PEG-30 Soysterol, PEG-20 Trioleate, PEG-40 Sorbitan Oleate, PEG-80 Sorbitan Laurate, Polysorbate 20, Polysorbate 80, POE-9 Lauryl Ether, These include, but are not limited to, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl L-oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG10-100 nonylphenol, PEG15-100 octylphenol, and poloxamer.

[0125] Suitable lipophilic surfactants include, by way of example only, fatty alcohols, glycerol fatty acid esters, acetylated glycerol fatty acid esters, lower alcohol fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, polyethylene glycol sorbitan fatty acid esters, sterols and sterol derivatives, polyoxyethylated sterols and sterol derivatives, polyethylene glycol alkyl ethers, sugar esters, sugar ethers, mono- and diglyceride lactic acid derivatives, the hydrophobic transesterification product of polyols and at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols, fat-soluble vitamins / vitamin derivatives, and mixtures thereof.In this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or the hydrophobic transesterification product of polyols and at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils and triglycerides.

[0126] In one embodiment, the composition may contain a solubilizing agent to ensure good solubilization and / or dissolution of the compound of the present invention and minimize precipitation of the compound of the present invention. This may be particularly important for compositions for parenteral use, such as injectable compositions. Solubilizing agents may also be added to increase the solubility of hydrophilic drugs and / or other components (e.g., surfactants) or to maintain the composition as a stable or homogeneous solution or dispersion.

[0127] Examples of suitable solubilizers include alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives, ethers of polyethylene glycol having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG, amides and other nitrogen-containing compounds, such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-acetylglucosamine, methyl ... Citrates 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 solubilizing agents known in the art such as, but not limited to, dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water.

[0128] A mixture of solubilizers may be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcyclodextrin, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol, and propylene glycol.

[0129] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer can be limited to a biologically acceptable amount, which can be easily determined by one skilled in the art. In some situations, for example, to maximize the drug concentration, it may be advantageous to include an amount of solubilizer that far exceeds the biologically acceptable amount, with the excess solubilizer being removed using conventional techniques such as distillation or evaporation before providing the composition to a subject. Thus, when present, the solubilizer can be present in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight based on the combined weight of the drug and other excipients. If desired, very small amounts of solubilizer, such as 5%, 2%, 1%, or even less, can also be used. Typically, the solubilizer may be present in an amount of about 1% to about 100% by weight, more typically about 5% to about 25% by weight.

[0130] The composition can further comprise one or more pharmaceutically acceptable additives and excipients, including, but not limited to, anti-adherents, anti-foaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicity agents, flavoring agents, coloring agents, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0131] In addition, acids or bases may be incorporated into the compositions to facilitate processing, enhance stability, or for other reasons. 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 are bases that are salts of pharmaceutically acceptable acids, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid. Salts of polybasic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate, can also be used. When the base is a salt, the cation can be any convenient pharmaceutically acceptable cation, such as ammonium, an alkali metal, or an alkaline earth metal. Examples include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0132] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, 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, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc.

[0133] Injectable pharmaceutical composition In some embodiments, the present invention provides an injectable pharmaceutical composition comprising a compound of the present invention and a pharmaceutical excipient suitable for injection, wherein the components and amounts of the drugs in the composition are as described herein.

[0134] Forms into which the novel compositions of the present invention can be incorporated for administration by injection include aqueous or oily suspensions or emulsions including sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical vehicles.

[0135] Aqueous solutions in physiological saline are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like.

[0136] Sterile injectable solution is prepared by incorporating the compound of the present invention in the required amount into a suitable solvent with various other ingredients as listed above, as needed, followed by filtration sterilization.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains a basic dispersion medium and the other necessary ingredients listed above.For the preparation of sterile powder for sterile injectable solution, the preferred method of preparation is vacuum drying and freeze-drying, which produces powder of active ingredient with any other desired ingredients from the solution that has been previously sterile-filtered.

[0137] Pharmaceutical Compositions for Topical (e.g., Transdermal) Delivery 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.

[0138] The composition of the present invention can be formulated into solid, semi-solid or liquid form preparations suitable for topical or local administration, such as gel, water-soluble jelly, cream, lotion, suspension, foam, powder, slurry, ointment, solution, oil, paste, suppository, spray, emulsion, saline, dimethyl sulfoxide (DMSO)-based solution, etc. Generally, carriers with higher density can provide areas with prolonged exposure to active ingredients.In contrast, solution formulations can provide more rapid exposure of active ingredients to selected areas.

[0139] The pharmaceutical compositions may also include suitable solid or gel phase carriers or excipients, which are compounds that allow for increased penetration of or assist in the delivery of therapeutic molecules across the stratum corneum permeability barrier of the skin. There are many of these penetration-enhancing molecules known to those skilled in the art of topical formulation.

[0140] Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidone, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0141] Another exemplary formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts, with or without other agents.

[0142] The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. ​​Such patches may be constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

[0143] Inhaled pharmaceutical composition Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions, preferably in pharmaceutically acceptable solvents, may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent 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.

[0144] Other pharmaceutical compositions Pharmaceutical compositions may also be prepared from the compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. The preparation of such pharmaceutical compositions is well known in the art. For example, Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002, Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990, Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw. See Hill, 20037ybg, Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001, Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000, Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999). all of which are incorporated herein by reference in their entirety.

[0145] The compounds or pharmaceutical compositions of the present invention can be administered by any method that allows delivery of the compound to the site of action. These methods include oral, intraduodenal, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal, or infusion), topical (e.g., transdermal application), rectal administration, administration via local delivery by catheter or stent, or administration via inhalation. The compounds can also be administered intraadiposely or intrathecally.

[0146] In some embodiments, the compounds or pharmaceutical compositions of the present invention are administered by intravenous injection.

[0147] The amount of compound administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the nature of the compound, and the discretion of the prescribing physician. However, effective dosages range from about 0.001 to about 100 mg / kg body weight / day, preferably from about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this amounts to about 0.05 to 7 g / day, preferably from about 0.05 to about 2.5 g / day. In some cases, dosage levels below the lower end of the aforementioned range may be more than sufficient, while in other cases, even higher doses may be used without causing adverse side effects, e.g., by dividing such higher doses into several smaller doses for administration throughout the day.

[0148] In some embodiments, the compounds of the invention are administered in a single dose.

[0149] Typically, such administration is by injection, e.g., intravenous injection, to rapidly introduce the drug. However, other routes may be used as appropriate. A single dose of the compound of the present invention may also be used to treat acute conditions.

[0150] In some embodiments, the compound of the present invention is administered in multiple doses. Dosing can be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing can be about once per month, once every two weeks, once per week, or once every other day. In another embodiment, the compound of the present invention and another agent are administered together about once per day to about six times per day. In another embodiment, administration of the compound of the present invention and another agent continues for less than about seven days. In yet another embodiment, administration continues for more than about six days, ten days, fourteen days, twenty-eight days, two months, six months, or one year. In some cases, continuous administration is achieved and maintained as long as necessary.

[0151] Administration of the compounds of the invention may continue for as long as necessary. In some embodiments, the compounds of the invention are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the compounds of the invention are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the compounds of the invention are administered chronically, for example, to treat chronic effects.

[0152] An effective amount of a compound of this invention can be administered by any of the accepted modes of administration for drugs with similar utilities, including rectal, buccal, intranasal and transdermal routes, by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant, in either a single dose or multiple doses.

[0153] The compositions of the present invention can also be delivered via impregnated or coated devices, such as stents, or cylindrical polymers inserted into the artery. Such administration methods can help prevent or ameliorate restenosis after procedures such as balloon angioplasty. Without being bound by theory, the compounds of the present invention can slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall, which contribute to restenosis. The compounds of the present invention can be administered by local delivery, for example, from the struts of a stent, from a stent graft, from a graft, or from the cover or sheath of a stent. In some embodiments, the compounds of the present invention are mixed with a matrix. Such a matrix may be a polymer matrix and may serve to bind the compound to the stent. Suitable polymer matrices for such uses include, for example, lactone-based polyesters or copolyesters (e.g., polylactides, polycaprolactone glycolides, polyorthoesters, polyanhydrides, polyamino acids, polysaccharides, polyphosphazenes, poly(ether-ester) copolymers (e.g., PEO-PLLA), polysiloxanes, poly(ethylene-vinyl acetate), acrylate-based polymers or copolymers (e.g., polyhydroxyethylmethylmethacrylate, polyvinylpyrrolidinone), fluorinated polymers such as polytetrafluoroethylene, and cellulose esters. Suitable matrices can be non-degradable or can degrade over time, allowing the compound to be transported. The compounds of the present invention can be applied to the surface of a stent by various methods, such as dipping / spin coating, spray coating, dip coating, and / or brush coating. The compounds may be applied in a solvent, and the solvent may be evaporated to form a layer of the compound on the stent. Alternatively, the compounds may be disposed within the body of the stent or graft, for example, within microchannels or micropores. Upon implantation, the compounds diffuse from the stent body and contact the arterial wall. Such stents can be prepared by dipping a stent fabricated to contain such micropores or microchannels into a solution of the compounds of the present invention in a suitable solvent, followed by evaporation of the solvent.Excess drug on the surface of the stent can be removed via a further brief solvent wash. In yet another embodiment, the compounds of the present invention can be covalently attached to a stent or graft. A covalent linker that decomposes in vivo, resulting in the release of the compounds of the present invention, can be used. For this purpose, any biolabile bond, such as an ester, amide, or anhydride bond, can be used. The compounds of the present invention can also be administered intravascularly from a balloon used during angioplasty. Extravascular administration of the compounds by pericarded or adventitial application of the formulations of the present invention can also be used to reduce restenosis.

[0154] Various stent devices that may be used as described are disclosed, for example, in the following references, all of which are incorporated herein by reference: U.S. Patent No. 5,451,233, U.S. Patent No. 5,040,548, U.S. Patent No. 5,061,273, U.S. Patent No. 5,496,346, U.S. Patent No. 5,292,331, U.S. Patent No. 5,674,278, U.S. Patent No. 3,657,744, U.S. Patent No. 4,739,762, U.S. Patent No. 5,195,984, U.S. Patent No. 5,292,331, U.S. Patent No. 5,674,278, U.S. Patent No. 5,879,382, and U.S. Patent No. 6,344,053.

[0155] The compound of the present invention can be administered according to dosage.It is known in the art that due to the inter-subject variability in compound pharmacokinetics, individualized dosing regimen is necessary for optimal treatment.The dosing of the compound of the present invention can be found by routine experiment in light of the present disclosure.

[0156] When a compound of the invention is administered in a composition containing one or more drugs, and the drugs have a shorter half-life than the compound of the invention, the unit dosage forms of the drugs and the compounds of the invention may be adjusted accordingly.

[0157] The pharmaceutical composition may be in a form suitable for oral administration as, for example, a tablet, capsule, pill, powder, sustained-release formulation, solution, or suspension; parenteral injection as a sterile solution, suspension, or emulsion; topical administration as an ointment or cream; or rectal administration as a suppository. The pharmaceutical composition may be in a unit dosage form suitable for single administration of a precise dose. The pharmaceutical composition comprises a conventional pharmaceutical carrier or excipient and a compound according to the present invention as an active ingredient. In addition, it may contain other medicinal or pharmaceutical agents, carriers, adjuvants, etc. Exemplary parenteral dosage forms include solutions or suspensions of the active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.

[0158] How to use The method typically involves administering a therapeutically effective amount of a compound of the present invention to a subject. The therapeutically effective amount of the combination of compounds of the present invention may vary depending on the intended application (in vitro or in vivo), or the subject and disease state to be treated (e.g., the subject's weight and age, the severity of the disease state, the mode of administration, etc.), and can be easily determined by one skilled in the art. The term also applies to a dose that induces a specific response in target cells, such as a decrease in proliferation or a downregulation of the activity of a target protein. The specific dose will vary depending on the particular compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system by which it is delivered.

[0159] In certain embodiments, the present invention provides pharmaceutical compositions comprising a bispecific compound or a pharmaceutically acceptable salt thereof.

[0160] In certain embodiments, the present invention provides pharmaceutical compositions comprising bispecific compounds for use in degrading target proteins in cells.

[0161] In certain embodiments, a method for degrading a target protein, comprising administering to a cell a therapeutically effective amount of a bispecific compound or a pharmaceutically acceptable salt thereof, wherein the compound is effective to degrade the target protein.

[0162] In certain embodiments, the present invention provides pharmaceutical compositions comprising bispecific compounds for use in the treatment or prevention of diseases or disorders in which SMARCA2 and / or SMARCA4 play a role.

[0163] In certain embodiments, the present invention provides pharmaceutical compositions comprising bispecific compounds for use in the treatment or prevention of diseases or disorders in which SWI / SNF mutations play a role.

[0164] In certain embodiments, the target protein is SMARCA2, SMARCA4, and / or PB1.

[0165] In certain embodiments, the target protein complex is SWI / SNF in a cell.

[0166] In certain embodiments, the SMARCA2 or SMARCA4 dependent disease or disorder comprises cancer.

[0167] In certain embodiments, the SWI / SNF complex dependent disease or disorder comprises cancer.

[0168] Exemplary cancers that may be treated with the compounds of the invention, either alone or in combination with at least one additional anti-cancer agent, include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular and renal cell carcinoma, cancer of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate and stomach; leukemia; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, Sarcomas, including myosinoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma; medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, and Schwannoma; colorectal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratocarcinoma.

[0169] In certain embodiments, cancers that may be treated using 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, B-cell precursor ALL, B-cell precursor lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, and Philadelphia chromosome positive CML.

[0170] In certain further embodiments, the cancer is a SMARCA2 and / or SMARAC4 dependent cancer.

[0171] In certain embodiments, the present invention provides pharmaceutical compositions comprising bispecific compounds for use when the SMARCA2 and / or SMARCA4 dependent disease or disorder is cancer.

[0172] The compounds of the present disclosure, as well as pharmaceutical compositions comprising them, can be administered alone or in combination with medical therapies, including, for example, surgery and radiation therapy (e.g., gamma irradiation, neutron radiation therapy, electron beam radiation therapy, proton radiation therapy, brachytherapy, systemic radioisotopes), to treat any of the diseases described.

[0173] In other aspects, the compounds of the present disclosure, as well as pharmaceutical compositions containing them, can be administered alone or in combination with one or more other agents to treat any of the diseases described.

[0174] In other methods, the compounds of the present disclosure, as well as pharmaceutical compositions containing them, can be administered in combination with an agonist of a nuclear receptor agent.

[0175] In other methods, the compounds of the present disclosure, as well as pharmaceutical compositions containing them, can be administered in combination with an antagonist of a nuclear receptor agent.

[0176] In other methods, the compounds of the present disclosure, as well as pharmaceutical compositions comprising them, can be administered in combination with an anti-proliferative agent.

[0177] Combination therapy To treat cancer and other proliferative diseases, the compounds of the present invention can be used in combination with chemotherapeutic agents, nuclear receptor agonists or antagonists, or other antiproliferative agents. The compounds of the present invention can also be used in combination with drug therapies such as surgery or radiation therapy (e.g., gamma irradiation, neutron radiation therapy, electron beam radiation therapy, proton radiation therapy, brachytherapy, and whole-body radioisotopes). Examples of suitable chemotherapeutic agents include abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, all-trans retinoic acid, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bendamustine, bevacizumab, bexarotene, bleomycin, bortezomib, bortezomib, intravenous busulfan, oral busulfan, castellon, capecitabine, carboplatin, carmustine, and cetaxel. Cimab, chlorambucil, cisplatin, cladribine, cloharabine, cyclophosphamide, cicarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, exemestane , fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, hisrelin acetate, ibritumomab tiuxetan acetate, idarubicin, ifosfamide, imatinib mesylate, interferon alfa-2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate Lolide, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panobinostat, panitumumab, pegaspagase, pegfilgrastim, pemetrexed disodium, pentostatin,Examples of the anticoagulant include pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronic acid.

[0178] In some embodiments, the compounds of the present invention can be used in combination with therapeutic agents that target epigenetic regulators. Examples of epigenetic regulators include bromodomain inhibitors, histone lysine methyltransferase inhibitors, histone arginine methyltransferase inhibitors, histone demethylase inhibitors, histone deacetylase inhibitors, histone acetylase inhibitors, and DNA methyltransferase inhibitors. Histone deacetylase inhibitors include, for example, vorinostat. Histone arginine methyltransferase inhibitors include inhibitors of protein arginine methyltransferases (PRMTs), such as PRMT5, PRMT1, and PRMT4. DNA methyltransferase inhibitors include inhibitors of DNMT1 and DNMT3.

[0179] For the treatment of cancer and other proliferative diseases, the compounds of the invention may be used in combination with targeted therapies including JAK kinase inhibitors (e.g., ruxolitinib), PI3 kinase inhibitors, including PI3K-delta selective and broad-spectrum PI3K inhibitors, cyclin-dependent kinase inhibitors, including MEK inhibitors, 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.

[0180] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), or PDR001. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is atezolizumab, durvalumab, or BMS-935559. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab.

[0181] 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).

[0182] The compounds of the present invention can be prepared using a number of preparative reactions known in the literature. The following schemes provide general guidance related to the preparation of the compounds of the present invention. Those skilled in the art will understand that they can use their general knowledge of organic chemistry to modify or optimize the preparations shown in the schemes 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.

[0183] The following examples are provided to illustrate some of the concepts described within this disclosure and are considered to provide embodiments, but should not be considered to limit the more general embodiments described herein. [Example]

[0184] General synthetic procedure The compounds described herein can be prepared according to the following synthetic schemes and general synthetic procedures. [ka]

[0185] Intermediate 1-6 (X1 = CO and X2 = CH2) can be synthesized according to the route described in Scheme 1. The S reaction between fluorophenyl 1-1 and amine 1-2 can be carried out by utilizing a suitable base (e.g., DIPEA, K2CO3, etc.) and heating in a suitable solvent (DMF, DMSO, THF, etc.). NAr can give compound 1-3. Reduction of the nitrile in 1-3 can be achieved under appropriate conditions (e.g., Raney nickel) to give 1-4. Reductive amination and cyclization of 1-4 with 1-5 (e.g., DIPEA, followed by AcOH and sodium triacetoxyborohydride) gives intermediate 1-6. [ka]

[0186] Intermediate 1-6 (X1 = CH2 and X2 = CO) can be synthesized according to the route described in Scheme 2. The S reaction between fluorophenyl 2-1 and amine 1-2 can be carried out using a suitable base (e.g., DIPEA, K2CO3, etc.) and heating in a suitable solvent (DMF, DMSO, THF, etc.). N Ar can give compound 2-2. Reduction of the nitrile in 2-2 can be achieved under appropriate conditions (e.g., Raney nickel) to give 2-3. Reductive amination and cyclization of 2-3 with 1-5 (e.g., DIPEA, followed by AcOH and sodium triacetoxyborohydride) gives intermediate 1-6. [ka]

[0187] Intermediate 1-6 (X1 and X2 = CO) can be synthesized according to the route described in Scheme 3. The S reaction between fluorophenyl 3-1 and amine 1-2 can be carried out using a suitable base (e.g., DIPEA, K2CO3, etc.) and heating in a suitable solvent (DMF, DMSO, THF, etc.). N Ar can give compounds 1-6. [ka]

[0188] Intermediate 1-6 (X1 = CO and X2 = CH2) can be synthesized according to the route described in Scheme 4. Halogenation of 4-1 (e.g., NBS and peroxide) in a suitable solvent (e.g., DCE) can provide compound 4-2. 4-2 can be converted to 4-3 using a suitable oxidizing agent (e.g., AgNO3 in water and IPA). Coupling of halide 4-3 with A2 (M = B(OH)2, B(OR)2, or SnR3) under standard cross-coupling conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and a base such as CsF, Na2CO3, or Cs2CO3) in a suitable solvent such as dioxane or DMF with or without water as a co-solvent provides intermediate 1-4. Reductive amination and cyclization of 1-4 with 1-5 (eg, DIPEA, followed by AcOH and sodium triacetoxyborohydride) gives compound 1-6. [ka]

[0189] Enantiomerically pure intermediate 5-3 (X1 = CO and X2 = CH2) can be synthesized according to the route described in Scheme 5. Reductive amination and cyclization of 1-4 with 5-1 (e.g., DIPEA, followed by AcOH and sodium triacetoxyborohydride) gives compound 5-2. Subsequent cyclization of 5-2 using a suitable base such as KOtBu gives intermediate 5-3. [ka]

[0190] Tricyclic intermediate 6-11 (R = H) can be synthesized according to the route described in Scheme 6. Protection of the -NH and -OH groups of commercially available starting material 6-1 with appropriate protecting groups (e.g., Boc, SEM, Bn, TBDMS, etc.), followed by esterification, affords ester 6-2. Conversion of 6-2 to 6-3 can be achieved using a reducing agent (e.g., LiAlH, DIBAL-H, etc.). Displacement of the hydroxyl group in 6-3 by conversion to a leaving group under appropriate conditions (e.g., TsCl / EtN, MsCl / EtN, etc.), followed by substitution (e.g., NaN) affords azide 6-4. Alternatively, compound 6-3 can be converted to azide 6-4 under Mitsunobu conditions ((PhO)PON, DEAD in THF). Deprotection of 6-4 (e.g., TFA or HCl for Boc deprotection) affords amine 6-5. S reaction between amine 6-5 and pyridazine 6-6 in the presence of a base such as DIPEA N The AR reaction affords intermediate 6-7. Reduction of the azide group in compound 6-7 via Staudinger reduction or hydrogenation, followed by intramolecular cyclization, affords compound 6-8. Protection of the -NH group and deprotection of -OPG then affords compound 6-9. Coupling of halide 6-9 with phenol 6-10 (M = B(OH)2, B(OR)2, or SnR3) under standard cross-coupling conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) and a base such as CsF, Na2CO3, or Cs2CO3) in a suitable solvent such as dioxane or DMF, with or without water as a co-solvent, affords intermediate 6-11. [ka]

[0191] Compounds of Formula (I) can also be synthesized according to the route described in Scheme 7. Mitsunobu reaction of the alcohol in compound 6-9 with A1 (Z = SH, OH, or NHR3) gives compound 7-1. Cross-coupling of halide 7-1 with phenol 6-10 (where the phenol is optionally protected), followed by deprotection, gives intermediate 7-2. Reaction of 7-2 with 1-6 (or 5-3) by either reductive amination or substitution gives compounds of Formula (I). [ka]

[0192] Compounds of formula (I) can also be made according to the route described in Scheme 8. Mesylation of the alcohol in compound 6-11, followed by substitution with A1 and deprotection, gives compound 7-2. Subsequent reductive amination of 7-2 with 1-6 (or 5-3) gives compounds of formula (I). [ka]

[0193] Compounds of formula (I) can also be made according to the route described in Scheme 9. Mesylation of the alcohol in compound 6-9 followed by displacement with A1 gives compound 7-1. Cross-coupling of halide 7-1 with phenol 9-1 followed by deprotection gives intermediate 7-2. Reaction of intermediate 7-2 with 1-6 (or 5-3) by either reductive amination or displacement gives compounds of formula (I). [ka]

[0194] Compounds of formula (I) can also be made according to the route described in Scheme 10. Mesylation of the alcohol in compound 6-9, followed by displacement with a cyanide (e.g., NaCN, KCN) affords nitrile 10-1. Cross-coupling of 10-1 with phenol 9-1, followed by deprotection, affords intermediate 10-2. Hydrolysis of the nitrile in 10-2, followed by amide coupling (e.g., HATU, DIPEA in DMF) affords compound 10-4 (L1 = CO). Reaction of 10-4 with 1-6 (or 5-3) via reductive amination affords compounds of formula (I). [ka]

[0195] Compounds of formula (I) can also be synthesized according to the route described in Scheme 11. Mesylation of the alcohol in compound 6-9 followed by substitution with NH2R3 gives compound 11-1. Scheme 11-1 of 11-1 with A1 (X = halogen) can be synthesized by the following route: N Ar affords compound 11-2. Cross-coupling of 11-2 with phenol 9-1 then affords intermediate 11-3. Reaction of 11-3 with 1-6 (or 5-3) via reductive amination affords compounds of formula (I). [ka]

[0196] Compounds of Formula (I) (where R≠H) can be synthesized according to the route outlined in Scheme 12. Esterification of commercially available acid 12-1, followed by alkylation, affords compound 12-3, which can be hydrolyzed to afford 12-4. Amide formation with 12-5 leads to intermediate 12-6, which can undergo deprotection and cyclization to afford tricycle 12-7. Reduction of the amide affords amine 6-8 (R≠R), which can then be converted to compounds of Formula (I) via the steps outlined in Schemes 6-11. Intermediate 1: (6aR,8S)-2-chloro-8-hydroxy-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl [ka]

[0197] Step 1: (2R,4S)-1-(tert-butoxycarbonyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylic acid [ka]

[0198] A round-bottom flask containing a solution of (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.0 g, 4.3 mmol) and imidazole (1.47 g, 21.6 mmol) in DCM (7 mL) and DMF (1.4 mL) was charged with tert-butyldimethylsilyl chloride (1.43 g, 9.51 mmol). The reaction mixture was stirred at room temperature for 18 hours, then poured into water, extracted with DCM (25 mL), and concentrated under reduced pressure. The residue was dissolved in 20% MTBE / hexane (v / v) (50 mL), washed with brine, and concentrated. The residue was dissolved in MeOH (7 mL) and THF (7 mL). Lithium hydroxide (176 mg) in water (9 mL) was added, and the mixture was stirred at room temperature for 3 hours. The mixture was poured into water, acidified with 1N HCl to pH ∼2, extracted with 20% MTBE / hexane (v / v) (3 × 50 mL), and washed with brine (50 mL). The organic fraction was dried over MgSO, filtered, and concentrated under reduced pressure to give (2R,4S)-1-(tert-butoxycarbonyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylic acid (estimated quantitative yield, 4.3 mmol). 11 H 24 NO3Si(M+2H-Boc) + LCMS calculated m / z: 246.2, found: 246.1.

[0199] Step 2: (2R,4S)-tert-butyl 4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate [ka]

[0200] A round-bottom flask containing a solution of (2R,4S)-1-(tert-butoxycarbonyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylic acid (1.5 g, 4.3 mmol) in THF (16 mL) at 0 °C was charged dropwise with BH SMe (0.82 mL, 8.6 mmol). The solution was allowed to warm to room temperature and stirred for 24 h. The reaction was quenched with saturated aqueous NH Cl, extracted with EtOAc (2 × 25 mL), washed with brine (25 mL), dried over MgSO, filtered, and concentrated under reduced pressure to give tert-butyl (2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (estimated quantitative yield, 4.3 mmol). 12 H 26 NO4Si(M+2H-tBu) + LCMS calculated m / z: 276.2, found: 276.0.

[0201] Step 3: (2R,4S)-tert-butyl 4-((tert-butyldimethylsilyl)oxy)-2-((tosyloxy)methyl)pyrrolidine-1-carboxylate [ka]

[0202] To a solution of tert-butyl (2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.4 g, 4.3 mmol) and 4-methylbenzenesulfonyl chloride (1.0 g, 5.4 mmol) in DCM (8.6 mL) at 0 °C was added pyridine (2.6 mL). The reaction was allowed to warm to room temperature and stirred for 23 h. The reaction was diluted with DCM and washed with water (2 × 50 mL), 10 wt% aqueous citric acid (2 × 50 mL), brine (50 mL), and dried over MgSO. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column (0-100% EtOAc / hexanes) to afford tert-butyl (2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-((tosyloxy)methyl)pyrrolidine-1-carboxylate (1.6 g, 3.3 mmol, 76% yield) as a clear oil. 18 H 32 NO4SSi(M+H-Boc) + LCMS calculated m / z: 386.2, found: 386.1.

[0203] Step 4: (2R,4S)-tert-butyl 2-(azidomethyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate [ka]

[0204] To a solution of tert-butyl (2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-((tosyloxy)methyl)pyrrolidine-1-carboxylate (500 mg, 1.0 mmol) in DMSO (5.1 mL) was added sodium azide (170 mg, 2.6 mmol). The reaction mixture was stirred at 65° C. for 22 hours. The reaction mixture was allowed to cool to room temperature, diluted with MTBE, and then washed with water (4×50 mL) and brine (50 mL). The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure to afford tert-butyl (2R,4S)-2-(azidomethyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate (343 mg, 94% yield) as a clear oil, which was used without further purification. 12 H 25 N4O3Si(M+H-tBu) + LCMS calculated m / z: 301.2, observed value: 301.0.

[0205] Step 5: (2R,4S)-2-(azidomethyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine [ka]

[0206] To a solution of tert-butyl (2R,4S)-2-(azidomethyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate (343 mg, 0.96 mmol) in DCM (1.5 mL) was added trifluoroacetic acid (1.5 mL, 19 mmol). The reaction mixture was stirred at room temperature for 1 hour and basified to pH 12 with 2N aqueous NaOH. The reaction mixture was extracted with DCM (3×25 mL), washed with brine (25 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give (2R,4S)-2-(azidomethyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine (165 mg, 67% yield) as a clear oil, which was used without further purification. 11 H 25 N4OSi(M+H) +LCMS calculated m / z: 257.2, found: 257.1.

[0207] Step 6: 4-((2R,4S)-2-(azidomethyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-3,6-dichloropyridazine [ka]

[0208] To a solution of (2R,4S)-2-(azidomethyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine (1.48 g, 5.8 mmol, 1.5 equiv) and 3,4,6-trichloropyridazine (124 mg, 0.68 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (120 μL, 0.71 mmol). The reaction was stirred at 80° C. for 20 h, then poured into water and extracted with EtOAc (2×25 mL). The combined organic layers were washed with water (4×50 mL), then brine (50 mL), then dried over MgSO and filtered. The filtrate was concentrated under reduced pressure to give 4-((2R,4S)-2-(azido-methyl)-4-((tert-butyldimethyl-silyl)oxy)pyrrolidin-1-yl)-3,6-dichloropyridazine (144 mg, 56% yield), which was used without further purification. 15 H 25 Cl2N6OSi(M+H) + LCMS calculated m / z: 403.1 / 405.1, found: 403.0 / 405.0. 1 H NMR(400MHz,DMSO)δ 7.41(s,1H),4.59(tt,J=7.6,3.7Hz,1H),4.56-4.51(m,1H),3.93(dd,J=11.3,3.4Hz,1H),3 .69(dd,J=13.2,4.5Hz,1H),3.39-3.28(m,5H),2.08-1.95(m,2H),0.77(s,9H),0.06(s,3H).

[0209] Step 7: (6aR,8S)-8-((tert-butyldimethylsilyl)oxy)-2-chloro-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine [ka]

[0210] To a solution of 4-((2R,4S)-2-(azidomethyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-3,6-dichloropyridazine (144 mg, 0.36 mmol) in THF (4 mL) was added triphenylphosphine (103 mg, 0.39 mmol). The reaction mixture was stirred at 60° C. for 80 min. Water (0.4 mL) and N,N-diisopropylethylamine (190 μL, 1.1 mmol) were added, and the reaction mixture was stirred at 60° C. for 24 h. The mixture was allowed to cool to room temperature and then extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give tert-butyl (6aR,8S)-8-((tert-butyl-dimethyl-silyl)oxy)-2-chloro-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine (120 mg crude, 0.36 mmol, estimated quantitative yield), which was used without further purification. 15 H 26 ClN4OSi(M+H) + LCMS calculated m / z: 341.2 / 343.2, found 341.0 / 342.9.

[0211] Step 8: (6aR,8S)-8-((tert-butyldimethylsilyl)oxy)-2-chloro-6a,7,8,9-tetrahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl ester [ka]

[0212] To a mixture of tert-butyl (6aR,8S)-8-((tert-butyldimethylsilyl)oxy)-2-chloro-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine (120 mg, 0.36 mmol, 1.0 equiv.) in DCM (3.6 mL) was added di-tert-butyl dicarbonate (234 mg, 1.1 mmol) and 4-(dimethylamino)pyridine (43.6 mg, 0.36 mmol). The mixture was stirred at room temperature for 1 hour and then charged with additional di-tert-butyl dicarbonate (156 mg, 0.71 mmol) and 4-(dimethylamino)pyridine (21.8 mg, 0.18 mmol). The mixture was stirred at room temperature for 20 min, then concentrated under reduced pressure and purified by silica gel chromatography (0–100% EtOAc / hexanes) to afford tert-butyl (6aR,8S)-8-((tert-butyl-dimethylsilyl)oxy)-2-chloro-6a,7,8,9-tetrahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (97 mg, 0.22 mmol, 62% yield) as a white solid. 20 H 34 ClN4O3Si(M+H) + LCMS calculated value m / z = 441.2 / 443.2, found value: 441.1 / 443.0.

[0213] Step 9: (6aR,8S)-2-chloro-8-hydroxy-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]-pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl ester

[0214] To a solution of tert-butyl (6aR,8S)-8-((tert-butyldimethylsilyl)oxy)-2-chloro-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (550 mg, 1.25 mmol) in THF (25 mL) at 0 °C was added tetrabutylammonium fluoride (1 M in THF, 3.1 mL, 3.1 mmol). The mixture was stirred at 0 °C for 5 minutes and then allowed to stir at room temperature for 19 hours. NHCl (saturated aqueous solution) was added to the reaction, and the mixture was extracted with DCM (3 × 25 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0–100% EtOAc / hexanes) to afford tert-butyl (6aR,8S)-2-chloro-8-hydroxy-6a,7,8,9-tetrahydropyrrolo-[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (251 mg, 0.77 mmol, 62% yield) as a yellow-orange solid. 14 H 20 ClN4O3(M+H) + LCMS calculated value m / z=327.1 / 329.1, found value: 327.0 / 328.9. Intermediate 2: 3-(1-oxo-6-(piperazin-1-yl)indolin-2-yl)piperidine-2,6-dione [ka]

[0215] Step 1: tert-Butyl 4-(4-cyano-3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate [ka]

[0216] To a solution of methyl 2-cyano-5-fluorobenzoate (5.00 g, 27.9 mmol) and tert-butyl 1-piperazinecarboxylate (15.6 g, 83.7 mmol) in NMP (20.0 mL) was added N,N-diisopropyl-ethylamine (7.29 mL, 41.9 mmol). The solution was heated at 120° C. for 4 hours and then cooled to −20° C. overnight. The observed solid product was filtered and washed with heptane to give tert-butyl 4-(4-cyano-3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate as a yellow solid. 13 H 16 N3O2(M-Boc+2H) + LCMS calculated value m / z = 246.1, observed value: 245.9

[0217] Step 2: tert-Butyl 4-(4-formyl-3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate [ka]

[0218] To a solution of tert-butyl 4-(4-cyano-3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (28.0 g, 81.1 mmol) in pyridine (39.3 mL, 486 mmol) and acetic acid (27.8 mL, 486 mmol) was added sodium phosphinate hydrate (17.2 g, 162 mmol) and water (10.0 mL), followed by Raney nickel (9.52 g, 162.14 mmol). The reaction was heated to 75° C. for 7 hours and monitored by HPLC, which confirmed only approximately 50% conversion. An additional 1.0 equivalent of Raney nickel was added and heated at 75° C. overnight. HPLC monitoring indicated approximately 94% conversion. The reaction was cooled, diluted with MeOH, filtered through Celite, and washed with MeOH. The filtrate was concentrated, then diluted in EtOAc and washed with water. The organic phase was dried over Na2SO4, filtered, and concentrated to give the crude material, which was purified by FCC (0% to 60% ethyl acetate / heptane) to give tert-butyl 4-(4-formyl-3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (13.5 g, 47.8%). 1 H NMR(300MHz,DMSO)δ 10.02(s,1H),7.8307.73(m,1H),7.17(dd,J=12.7,2.5Hz,2H),3.86(s,3H),3.44(s,8H),3.32(s,2H),1.42(s,9H).

[0219] Step 3: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazine-1-carboxylate [ka]

[0220] To a solution of tert-butyl 4-(4-formyl-3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (3.20 g, 9.19 mmol) in DCM (20.0 mL) and DMF (5.00 mL) was added N,N-diisopropylethylamine (1.92 mL, 11.1 mmol) and pyroglutamine (1.18 g, 9.19 mmol). The reaction was stirred at room temperature for 1 hour, and acetic acid (5.25 mL, 91.9 mmol) was added to the solution. The reaction was stirred for an additional hour, and sodium triacetoxyborohydride (5.84 g, 27.6 mmol) was added. The reaction was stirred overnight and monitored by HPLC to confirm complete conversion. The reaction was stopped, diluted with DCM (50.0 mL), and quenched with saturated NaHCO solution dropwise until a pH of 8-9 was maintained. The organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude material, which was purified by FCC (0% to 80% EA / heptane) to give tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazine-1-carboxylate (3.00 g, 76.3%). 22 H 29 N4O5(M+H) + LCMS calculated m / z=429.2, found: 428.9.

[0221] Step 4: 3-(1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

[0222] To a solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazine-1-carboxylate (3.80 g, 8.87 mmol) in DCM (80 mL) was added 2,2,2-trifluoroacetic acid; TFA (20 mL, 261.36 mmol) dropwise at 0 °C. The reaction was stirred at room temperature for 3 h, and complete conversion was observed by HPLC. The DCM and TFA were concentrated and then further diluted with 10 mL of CHCl3:IPA (3:1). To this solution, 10% Na2CO3 was added dropwise at 0 °C, and the formation of a precipitate was observed at a pH of about 8-9. The solid was filtered and dried to give the desired product, 3-(1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (2.60 g, 89.3%). 17 H 21 N4O3(M+2H-Boc) + LCMS calculated value m / z = 329.2, found value: 329.1 Intermediate 3: 1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-4-carbaldehyde [ka]

[0223] Step 1: Methyl 5-amino-4-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate [ka]

[0224] The title compound was prepared using procedures similar to those described for Intermediate 2, Steps 1-3, using the appropriate starting materials.

[0225] Step 2: 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0226] A 1.0 M solution of potassium t-butoxide in THF (8.30 mL, 8.30 mmol) was added to a solution of 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 h. The reaction was warmed to 0° C. and the pH was carefully adjusted to approximately 3 using 1 N aqueous HCl. To this solution was carefully added saturated aqueous NaHCO dropwise to adjust the pH to approximately 6. DCM was added and the phases were separated. The combined organics were washed with water, dried over MgSO, filtered, and concentrated under reduced pressure. The crude material was triturated with DCM (5.00 mL), followed by MTBE (20.0 mL), upon which a white precipitate crashed out. The solid was filtered and dried via vacuum filtration to give 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.89 g, 68% yield). 1 H NMR(300MHz,DMSO)δ 10.97(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),2.38(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).

[0227] Step 3: 1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-4-carbaldehyde

[0228] 2,2,2-Trifluoroacetic acid (2.38 mL, 31.1 mmol) was added to a solution of 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 (9.34 mL) and acetone (3.11 mL). The reaction was stirred overnight. The reaction mixture was concentrated under reduced pressure to give 1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-4-carbaldehyde (440 mg, quantitative yield) as the TFA salt. 19 H 22 N3O4(M+H) + LCMS calculated m / z=356.2, found: 356.2. Intermediate 4: (1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-4-yl) 4-methylbenzenesulfonate methyl ester [ka]

[0229] Step 1: Methyl 2-cyano-5-(4-(hydroxymethyl)piperidin-1-yl)benzoate [ka]

[0230] To a solution of methyl 2-cyano-5-fluorobenzoate (2.00 g, 11.2 mmol) and 4-piperidine-methanol (1.67 g, 14.5 mmol) in dimethyl sulfoxide (22.3 mL) was added N,N-diisopropyl-ethylamine (5.83 mL, 33.5 mmol). The reaction mixture was heated to 110 °C and stirred for 1.5 h. The product mixture was diluted with EtOAc (100 mL) and transferred to a separatory funnel. The diluted reaction mixture was washed with saturated aqueous 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 silica gel flash column chromatography eluting with a gradient of 0 to 100% EtOAc / hexane to afford methyl 2-cyano-5-(4-(hydroxymethyl)piperidin-1-yl)benzoate (3.02 g, 98% yield) as a yellow oil. 15 H 18 N2O3[M+H] + LCMS calculated for: m / z=275.1, found: 275.1.

[0231] Step 2: Methyl 2-formyl-5-(4-(hydroxymethyl)piperidin-1-yl)benzoate [ka]

[0232] To a solution of methyl 2-cyano-5-(4-(hydroxymethyl)piperidin-1-yl)benzoate (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 Celite, and the Celite 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 layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography eluting with a gradient of 0-100% EtOAc / 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 NO4[M+H] + LCMS calculated for: m / z=278.1, found: 278.1.

[0233] Step 3: 3-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0234] To a stirred solution of methyl 2-formyl-5-(4-(hydroxymethyl)piperidin-1-yl)benzoate (2.40 g, 8.65 mmol) in DCM (48.8 mL) and DMF (48.8 mL) was added 3-aminopiperidine-2,6-dione hydrochloride (1.85 g, 11.3 mmol), followed by N,N-diisopropylethylamine (3.77 mL, 21.6 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled to 0° C. and acetic acid (5.94 mL, 104 mmol) was added, followed by sodium triacetoxyborohydride (5.50 g, 26.0 mmol). The reaction mixture was allowed to warm slowly to room temperature and stirred for an additional 3 hours. The reaction mixture was diluted with water (10 mL), and the solution was basified with saturated aqueous NaHCO until no further gas evolution was observed. The basified product mixture was filtered and the solid was washed with water (10 mL x 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 N3O4[M+H] + LCMS calculated for: m / z=358.2, found: 358.1.

[0235] Step 4: Methyl (1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-4-yl) 4-methylbenzenesulfonate

[0236] Tosyl chloride (107 mg, 0.560 mmol) was added to a solution of 3-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 0.280 mmol) in pyridine (3.00 mL). The reaction was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM, and the organics were washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography eluting with a gradient of 0-100% EtOAc / DCM to afford methyl (1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-4-yl)4-methylbenzenesulfonate (43.7 mg, 31%) as an off-white solid. 19 H 23 N3O4[M+H] + LCMS calculated for: m / z=512.4, found: 511.7. Intermediate 5: 3-(1-oxo-6-(piperidin-4-yl)indolin-2-yl)piperidine-2,6-dione [ka]

[0237] Step 1: Methyl 5-bromo-2-(dibromomethyl)benzoate [ka]

[0238] A suspension of methyl 5-bromo-2-methylbenzoate (6.08 g, 26.6 mmol), NBS (14.0 g, 79.7 mmol), and benzoyl peroxide (0.32 g, 1.33 mmol) in DCE (60.0 mL) was stirred at 80 °C for 18 h. The reaction mixture was cooled to ambient temperature, diluted with DCM (140 mL), washed with 10% NaSO solution (100 mL), saturated NaHCO solution (100 mL), water (100 mL), and brine (100 mL), then dried over NaSO, filtered, and concentrated. The residue was dried under high vacuum to give the desired product, methyl 5-bromo-2-(dibromomethyl)benzoate (9.875 g, 96.1%), as a pale yellow solid. 1 H NMR(300MHz,CDCl3)δ 8.04(dd,J=5.4,3.1Hz,2H),7.97(s,1H),7.74(dd,J=8.6,2.1Hz,1H),3.96(s,3H).

[0239] Step 2: Methyl 5-bromo-2-formylbenzoate [ka]

[0240] Silver nitrate (6.57 g, 38.7 mmol) was dissolved in water (60.0 mL). This solution was added dropwise to a stirred solution of methyl 5-bromo-2-(dibromomethyl)benzoate (5.99 g, 15.5 mmol) in IPA (60.0 mL) at 0 °C. The resulting mixture was stirred in the dark at ambient temperature for 4 h when HPLC showed the disappearance of the starting material. The precipitated silver salts were removed by filtration and washed with a small amount of IPA. The IPA was evaporated under reduced pressure, and the remaining aqueous phase was extracted with EtOAc (50.0 mL × 3). The combined organic phases were washed with water (50.0 mL), brine (50.0 mL), then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dried under high vacuum to give the desired product, methyl 5-bromo-2-formylbenzoate (3.26 g, 13.4 86.8%), as a white solid. C9H8BrO3(M+H) + LCMS calculated for: m / z=242.9, found: 242.8.1 H NMR(300MHz,CDCl3)δ 10.58(s,1H),8.13(d,J=1.5Hz,1H),7.85-7.76(m,2H),3.99(s,3H).

[0241] Step 3: tert-Butyl 4-(4-formyl-3-methoxycarbonylphenyl)-3,6-dihydro-2H-pyridine-1-carboxylate [ka]

[0242] When HPLC showed complete conversion of the starting material, a suspension of N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (5.55 g, 17.9 mmol), methyl 5-bromo-2-formylbenzoate (2.91 g, 12.0 mmol), Pd(dppf)Cl (0.44 g, 0.6 mmol), and CsOAc (9.18 g, 47.8 mmol) in 1,4-dioxane (40.0 mL) and water (10.0 mL) was heated at 95 °C for 1.5 h under a N atmosphere. The reaction was cooled to ambient temperature and partitioned between EtOAc and water (100 mL each). The organic layer was separated, and the aqueous layer was extracted with EtOAc (50 mL × 3). The combined organic phases were washed with water and brine (100 mL each), dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (0-25% EtOAc in heptane) to give the desired product, tert-butyl 4-(4-formyl-3-methoxycarbonylphenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (3.30 g, 79.9%) as a yellow solid. f =0.4 (25% EtOAc in heptane). 1 H NMR(300MHz,CDCl3)δ 10.57(s,1H),7.93(t,J=4.8Hz,2H),7.63(dd,J=8.1,1.5Hz,1H),6.25(s,1H),4.12(d ,J=2.8Hz,2H),3.98(s,3H),3.66(t,J=5.7Hz,2H),2.56(d,J=1.4Hz,2H),1.49(s,9H).

[0243] Step 4: tert-Butyl 4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate [ka]

[0244] To a suspension of tert-butyl 4-(4-formyl-3-methoxycarbonylphenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (310 mg, 0.900 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (185 mg, 1.12 mmol) in DCM (4 mL) and DMF (2 mL) was slowly added DIPEA (0.47 mL, 2.69 mmol), and the resulting mixture was stirred at ambient temperature for 30 minutes. AcOH (0.31 mL, 5.39 mmol) was then added, and the mixture was stirred for 1 hour. NaBH(OAc) (571 mg, 2.69 mmol) was added in several portions, and the reaction was stirred at ambient temperature for 18 hours. The reaction was diluted with DCM (150 mL), washed with saturated NaHCO solution, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (0-5% MeOH in DCM) to give the desired product, tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (290 mg, 75.9%) as a white solid. Rf =0.3 (5% MeOH in DCM). C 23 H 28 N3O5(M+H) + LCMS calculated for: m / z=426.2, found: 426.0. 1H NMR(300MHz,DMSO)δ 10.99(s,1H),7.77-7.69(m,2H),7.58(d,J=8.5Hz,1H),6.28(s,1H),5.13(dd,J=13.2,5.1Hz,1H),4.39(dd,J=41.6,17.4Hz,2H),4 .02(s,2H),3.57(dd,J=10.6,5.1Hz,2H),3.00-2.84(m,1H),2.71-2.54(m,3H),2.46-2.31(m,1H),2.07-1.95(m,1H),1.43(s,9H).

[0245] Step 5: tert-Butyl 4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]piperidine-1-carboxylate [ka]

[0246] tert-Butyl 4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (290 mg, 0.680 mmol) in MeOH (5.00 mL) and THF (5.00 mL) was hydrogenated over 10% Pd / C under 30 psi for 2 hours. The solid material was removed by filtration and washed with a small amount of MeOH. The filtrate was concentrated, and the residue was purified by flash column chromatography on silica gel (0 to 4% MeOH in DCM) to afford tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]piperidine-1-carboxylate (265 mg, 90.9%) as a white solid. f =0.25 (5% MeOH in DCM). C 23 H 30 N3O5(M+H) + LCMS calculated for: m / z=428.2, found: 427.9. 1H NMR(300MHz,DMSO)δ 10.99(s,1H),7.55(d,J=11.3Hz,3H),5.11(dd,J=13.2,5.0Hz,1H),4.35(dd,J=41.1,17.1Hz,2H),4.09(d,J=12.2Hz,2H),2.98-2.79(m,3H),2. 70-2.55(m,2H),2.39(ddd,J=26.2,13.3,4.3Hz,1H),1.98(dd,J=11.3,4 .6Hz,1H),1.83-1.73(m,2H),1.65-1.49(m,2H),1.40(d,J=11.4Hz,9H).

[0247] Step 6: 3-(1-oxo-6-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0248] The title compound was prepared using a procedure similar to that described for Intermediate 2, Step 4, replacing tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazine-1-carboxylate with tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]piperidine-1-carboxylate. 18 H 22 N3O3[M+H] + LCMS calculated for: m / z=328.2, found: 328.1. Intermediate 6: (S)-3-(1-oxo-6-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione [ka]

[0249] Step 1: (S)-tert-butyl 4-(2-(1-amino-5-methoxy-1,5-dioxopentan-2-yl)-3-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate [ka]

[0250] To a suspension of tert-butyl 4-(4-formyl-3-methoxycarbonylphenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (Intermediate 5, Step 3) (2.88 g, 8.34 mmol) and H-Glu(OMe)-NH hydrochloride (2.05 g, 10.4 mmol) in DCM (40 mL) was slowly added DIPEA (4.36 mL, 25.0 mmol), and the resulting mixture was stirred at ambient temperature for 30 min. AcOH (2.86 mL, 50.0 mol) was then added, and the mixture was stirred for 1 h. NaBH(OAc) (5.30 g, 25.0 mmol) was added in several portions, and the reaction was stirred at ambient temperature for 18 h. The reaction was diluted with DCM (150 mL), washed with saturated NaHCO solution, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (0-5% MeOH in DCM) to give the desired product, tert-butyl (S)-4-(2-(1-amino-5-methoxy-1,5-dioxopentan-2-yl)-3-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3.01 g, 78.9%) as a white solid. f =0.3 (5% MeOH in DCM). C 24 H 32 N3O6(M+H) + LCMS calculated for: m / z=458.2, found: 458.1. 1 H NMR(300MHz,DMSO)δ 7.75-7.67(m,2H),7.57(d,J=8.3Hz,2H),7.20(s,1H),6.26(s,1H),4.75(dd,J=10.2,4.6Hz,1H),4.52(dd,J=45.0,17. 7Hz,2H),4.02(d,J=7.1Hz,2H),3.56(t,J=5.5Hz,2H),3.50(s,3H),2.58-2.50(m,2H),2.29-1.96(m,4H),1.43(s,9H).

[0251] Step 2: (S)-tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3,6-dihydro-pyridine-1(2H)-carboxylate [ka]

[0252] To tert-butyl (S)-4-(2-(1-amino-5-methoxy-1,5-dioxopentan-2-yl)-3-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.01 g, 2.20 mmol) in THF (15.0 mL) was added t-BuOK (1.0 M in THF, 2.75 mmol, 2.75 mL) dropwise at −78° C. The resulting mixture was stirred at −78° C. for 2 hours. The reaction was quenched by adding 1 N HCl solution to pH 6 and extracted with DCM (50 mL × 3). The combined organic phases were washed with brine (50 mL), dried over NaSO, filtered, and concentrated. The residue was suspended in a minimum amount of DCM (2.00 mL), and MTBE (20.0 mL) was added at 0° C. The white precipitate was filtered off and washed with cold MTBE. The filter cake was dried under a stream of air to give tert-butyl (S)-4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (718 mg, 1.69 mmol, 76.7% yield) as a white solid. 19 H 20 N3O5(M+2H- t Bu) + LCMS calculated for: m / z = 370.14, found: 370.09. 1H NMR(300MHz,DMSO)δ 10.99(s,1H),7.75-7.71(m,2H),7.58(d,J=8.5Hz,1H),6.28(s,1H),5.13(dd,J=13.2,5.1Hz,1H),4.39(dd,J=41.6,17.5Hz,2H),4.02(s,2H) ),3.56(t,J=5.6Hz,2H),3.01-2.83(m,1H),2.71-2.51(m,3H),2.40(qd,J=13.3,4.5Hz,1H),2.01(ddd,J=10.2,5.1,3.1Hz,1H),1.43(s,9H).

[0253] Step 3: (S)-tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-1-carboxylate [ka]

[0254] (S)-tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (818 mg, 1.92 mmol) in MeOH (5.00 mL) and THF (5.00 mL) was hydrogenated over 10% Pd / C under 30 psi for 2 hours. The solid material was filtered off and washed with a small amount of MeOH. The filtrate was concentrated, and the residue was purified by flash column chromatography on silica gel (0 to 4% MeOH in DCM) to give (S)-tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-1-carboxylate (809 mg, 98.4%) as a white solid. Rf =0.25 (5% MeOH in DCM). C 19 H 22 N3O5(M+2H-tBu) + LCMS calculated for: m / z=372.2, found: 372.0. 1H NMR(300MHz,DMSO)δ 10.99(s,1H),7.55(d,J=11.0Hz,3H),5.11(dd,J=13.3,5.1Hz,1H),4.35(dd,J=41.3,17.1Hz,2H),4.08(d,J=10.3Hz,2H),2.99-2.74(m,4 H),2.59(dd,J=15.4,2.2Hz,1H),2.39(qd,J=13.1,4.3Hz,1H),2.10-1.92(m,1H),1.79(d,J=12.1Hz,2H),1.66-1.45(m,2H),1.42(s,9H).

[0255] Step 4: (S)-3-(1-oxo-6-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione; hydrochloride salt

[0256] (S)-tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-1-carboxylate (809 mg, 1.89 mmol) was suspended in 1,4-dioxane (2.00 mL) and 4N HCl in 1,4-dioxane (15.0 mL) was added at 0° C. The reaction was stirred at ambient temperature for 18 hours. The white precipitate was removed by filtration and washed with a small amount of cold 1,4-dioxane. The filter cake was dried under a stream of air to give (S)-3-(1-oxo-6-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (688 mg, quantitative) as a white solid. C 18 H 22 N3O3(M+H) + LCMS calculated for: m / z=328.2, found: 328.1. Intermediate 7: (S)-3-(1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione; hydrochloride [ka]

[0257] Step 1: tert-Butyl 4-(4-cyano-3-methoxycarbonylphenyl)piperazine-1-carboxylate [ka]

[0258] To a solution of methyl 2-cyano-5-fluorobenzoate (20.0 g, 112 mmol) and tert-butyl 1-piperazinecarboxylate (31.2 g, 167 mmol) in NMP (20.0 mL) was added N,N-diisopropyl-ethylamine (0.01 mL, 0.04 mmol) and heated to 120° C. for 4 hours. HPLC monitoring after 4 hours indicated consumption of the starting material. The reaction mixture was cooled to −20° C. overnight, and the product crashed out. The solid was filtered and washed with heptane to give a yellow solid as the desired product, tert-butyl 4-(4-cyano-3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (28.0 g, 72.6%). 13 H 16 N3O2(M+2H-Boc) + LCMS calculated for: m / z = 246.17, found: 245.99. 1 H NMR(300MHz,DMSO)δ 7.73(d,J=8.8Hz,1H),7.47(d,J=2.7Hz,1H),7.22(dd,J=8.8,2.7Hz,1H),3.89(s,3H),3.51-3.38(m,8H),1.42(s,9H).

[0259] Step 2: tert-Butyl 4-(4-formyl-3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate [ka]

[0260] To a solution of tert-butyl 4-(4-cyano-3-methoxycarbonylphenyl)piperazine-1-carboxylate (8.10 g, 23.5 mmol) in pyridine (11.4 mL, 141 mmol) and acetic acid (8.05 mL, 141 mmol) was added sodium hypophosphinate monohydrate (4.97 g, 46.9 mmol) and water (10.0 mL). To the stirred solution was added Raney nickel (2.75 g, 46.9 mmol) in multiple portions to avoid emulsion formation. The reaction was heated to 75°C for 7 hours and monitored by HPLC, which confirmed only approximately 50% conversion. An additional 1.0 equivalent of Raney nickel was added to the solution and heated at 75°C overnight. HPLC monitoring indicated approximately 94% conversion. Heating was stopped, and the reaction was cooled, diluted with MeOH, filtered through Celite, and washed with MeOH to remove the Raney nickel. The filtrate was concentrated to remove pyridine and MeOH. The concentrated solution was then washed with water. The organic phase was dried over Na2SO4, filtered, and concentrated to give the crude product. Purification by FCC (0% to 60% EA / heptane) gave a yellowish solid as the desired product, tert-butyl 4-(4-formyl-3-methoxy-carbonylphenyl)piperazine-1-carboxylate (5.00 g, 61.1%). 18 H 25 N2O5(M+H) + LCMS calculated for: m / z=349.2, found: 348.9. 1 H NMR(300MHz,CDCl3)δ 10.34(s,1H),7.92(d,J=8.8Hz,1H),7.26(d,J=1.6Hz,1H),7.00(dd,J=8.8,2.6H z,1H),3.96(s,3H),3.66-3.55(m,4H),3.39(dd,J=13.4,8.6Hz,4H),1.48(s,9H).

[0261] Step 3: (S)-tert-butyl 4-(2-(1-amino-5-methoxy-1,5-dioxopentan-2-yl)-3-oxoisoindolin-5-yl)piperazine-1-carboxylate [ka]

[0262] To a solution of tert-butyl 4-(4-formyl-3-methoxycarbonylphenyl)piperazine-1-carboxylate (4.20 g, 12.0 mmol) in DCM (50.0 mL) was added N,N-diisopropylethylamine (5.25 mL, 30.1 mmol) and methyl (4S)-4,5-diamino-5-oxopentanoate (2.32 g, 14.5 mmol). The reaction was stirred at room temperature for 1 hour, and acetic acid (6.89 mL, 121 mmol) was added to the solution. The reaction was stirred for an additional hour, and sodium triacetoxyborohydride (7.66 g, 36.2 mmol) was added. The reaction was stirred overnight and complete conversion was confirmed by HPLC. The reaction was diluted with DCM (30.0 mL) and quenched with water (30.0 mL). Further extraction was performed with DCM (30 mL x 2). The organic phase was dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was further purified by FCC (0% to 7% MeOH / DCM) to give the desired compound (S)-4-(2-(1-amino-5-methoxy-1,5-dioxopentan-2-yl)-3-oxoisoindolin-5-yl)piperazine-1-carboxylate tert-butyl ester (3.80 g, 68.5%) as a white solid. 23 H 33 N4O6(M+H) + LCMS calculated for: m / z=461.2, found: 461.1. 1 H NMR(300MHz,CDCl3)δ 7.33(dd,J=10.8,5.3Hz,2H),7.16(dd,J=8.4,2.4Hz,1H),6.40(s,1H),5.58(s,1H),5.00-4.83(m,1H),4.39(q,J=16.8H) z,2H),3.63(s,3H),3.62-3.55(m,4H),3.22-3.13(m,4H),2.49-2.28(m,3H),2.20(tt,J=11.4,8.2Hz,1H),1.49(s,9H).

[0263] Step 4: (S)-tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazine-1-carboxylate [ka]

[0264] To a solution of tert-butyl (S)-4-(2-(1-amino-5-methoxy-1,5-dioxopentan-2-yl)-3-oxoisoindolin-5-yl)piperazine-1-carboxylate (3.80 g, 8.25 mmol) in THF (80.0 mL) was added potassium t-butoxide (1.0 M in THF, 9.90 mL, 9.90 mmol) at −78° C. The reaction was stirred at −78° C. for 3 hours. The reaction temperature was maintained at 0° C. and quenched by adding 1 N HCl to reach pH 3. To this solution, NaHCO (saturated aqueous solution) was slowly added dropwise to reach pH 6. The reaction mixture was then further diluted with DCM and washed with water. The aqueous phase was further extracted with DCM. The organic phase was collected, dried over NaSO, filtered, and concentrated to give the crude product. (S)-tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazine-1-carboxylate (2.90 g, 82.0%). The crude product was approximately 96% pure (HPLC) and was carried on to the next step without further purification. 18 H 21 N4O5(M+2H- t Bu) + LCMS calculated value for: m / z=373.2, actual value: 373.0. 1H NMR (300MHz, CDCl3)δ 8.06(s,1H),7.37(dd,J=9.3,5.3Hz,2H),7.17(dd,J=8.4,2.3Hz,1H),5.22(dd,J=13.1,5.2Hz,1H),4.35(dd, J=43.1,15.6Hz,2H),3.72-3.49(m,4H),3.30-3.13(m,4H),2.96-2.73(m,2H),2.43-2.15(m,2H),1.49(s,9H).

[0265] Step 5: (S)-3-(1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione [ka]

[0266] To a round-bottom flask containing tert-butyl (S)-4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazine-1-carboxylate (4.3 g, 10.0 mmol), 4N HCl in dioxane (34.0 mL, 136 mmol) was added at 0° C. The solution was stirred at 0° C. for 3 hours to room temperature to ensure complete conversion. The precipitate was filtered and dried under a stream of air to give (S)-3-(1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione; hydrochloride salt (3.30 g, 90.1%). 17 H 21 N4O3(M+H) + LCMS calculated for: m / z=329.2, found: 329.0. 1 H NMR(300MHz,DMSO)δ 10.98(s,1H),9.27(s,2H),7.49(d,J=8.3Hz,1H),7.39-7.19(m,2H),5.10(dd,J=13.2,5.1Hz,1H),4.27(dt,J=27.7,13.9 Hz,2H),3.49-3.40(m,4H),3.22(s,4H),2.98-2.83(m,1H),2.59(d,J=16.3Hz,1H),2.46-2.27(m,1H),2.09-1.94(m,1H). Intermediates 8a and 8b: (6aR,8R)-8-(benzyloxy)-2-chloro-6a-ethyl-6a,7,8,9-tetrahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-6(5H)-one and (6aS,8R)-8-(benzyloxy)-2-chloro-6a-ethyl-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-6(5H)-one [ka]

[0267] Step 1: 1-(tert-butyl) 2-methyl (4R)-4-(benzyloxy)-2-ethylpyrrolidine-1,2-dicarboxylate [ka]

[0268] To 1-(tert-butyl) 2-methyl(2R,4R)-4-(benzyloxy)pyrrolidine-1,2-dicarboxylate (2.00 g, 5.96 mmol) in THF (55 mL) was slowly added LiHMDS (12 mL, 12 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 1 hour, after which ethyl iodide (1.9 mL, 23.6 mmol) was added. The reaction was stirred at −78° C. for 5 minutes and then allowed to warm slowly to room temperature with stirring. After 3.5 hours, the reaction was quenched with MeOH (55 mL). A solution of NaOH (1.91 g, 47.7 mmol) in water (55 mL) was added, and the mixture was stirred at room temperature for 20 minutes and then poured into water. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine (1x), then concentrated and purified via SiO2 FCC (0-30% EtOAc in hexanes) to give 1-(tert-butyl) 2-methyl (4R)-4-(benzyloxy)-2-ethylpyrrolidine-1,2-dicarboxylate (1.11 g, 51%). 15 H 22 NO3[M-Boc+2H] + LCMS calculated for: m / z=264.2, found: 264.0.

[0269] Step 2: (4R)-4-(benzyloxy)-1-(tert-butoxycarbonyl)-2-ethylpyrrolidine-2-carboxylic acid [ka]

[0270] To 1-(tert-butyl) 2-methyl(4R)-4-(benzyloxy)-2-ethylpyrrolidine-1,2-dicarboxylate (2.72 g, 7.48 mmol) in 1:1 THF / MeOH (40 mL) was added a solution of NaOH (2.99 g, 74.8 mmol) in water (20 mL). The reaction was stirred at 75° C. for 2.5 hours and then allowed to cool to room temperature. The mixture was poured into water and then extracted with MTBE (3×). The combined organic layers were washed with water (2×). The combined aqueous layers were extracted once more with MTBE and then acidified to a pH of less than 2 with 2N HCl (aq), followed by extraction with EtOAc (3×). The combined EtOAc layers were washed with brine, dried over MgSO, filtered, and concentrated to give crude (4R)-4-(benzyloxy)-1-(tert-butoxycarbonyl)-2-ethylpyrrolidine-2-carboxylic acid (estimated quantitative yield) as a yellow oil. 14 H 20 NO3[M-Boc+2H] + LCMS calculated value for: m / z=250.1, found value: 250.0.

[0271] Step 3: tert-butyl (2R,4R)-4-(benzyloxy)-2-((4-bromo-6-chloropyridazin-3-yl)carbamoyl)-2-ethylpyrrolidine-1-carboxylate and tert-butyl (2S,4R)-4-(benzyloxy)-2-((4-bromo-6-chloropyridazin-3-yl)carbamoyl)-2-ethylpyrrolidine-1-carboxylate [ka]

[0272] To crude 1-(tert-butyl) 2-methyl(4R)-4-(benzyloxy)-2-ethylpyrrolidine-1,2-dicarboxylate (672 mg, 1.43 mmol) and N,N-diisopropylethylamine (1.21 mL, 6.92 mmol) in MeCN (10 mL) was added HATU (880 mg, 2.31 mmol). The reaction was stirred at room temperature for 20 minutes and then concentrated. The residue was taken up in THF (8 mL), and then 4-bromo-6-chloropyridazin-3-amine (802 mg, 3.85 mmol) was added, followed by NaH (60% dispersion in mineral oil, 385 mg, 9.62 mmol). After rinsing the sides of the flask with THF (2 mL), the reaction was stirred at room temperature for 50 minutes, then cooled to 0 °C and quenched with saturated NH4Cl (aq). The mixture was poured into water and then extracted with EtOAc (3x). The combined organic layers were washed with brine (1x) and then concentrated. The residue was purified via SiO2FCC (0-100% EtOAc in hexanes) to give "Diastereomer A" (2R,4R)-4-(benzyloxy)-2-((4-bromo-6-chloropyridazin-3-yl)carbamoyl)-2-ethylpyrrolidine-1-carboxylate (473 mg, 46%) and "Diastereomer B" (2S,4R)-4-(benzyloxy)-2-((4-bromo-6-chloropyridazin-3-yl)carbamoyl)-2-ethylpyrrolidine-1-carboxylate (286 mg, 28%). 23 H 29 BrClN4O4[M+H] + LCMS calculated for: m / z=539.1, found: 539.0 (diastereomer A) and 539.0 (diastereomer B).

[0273] Step 4: (6aR,8R)-8-(benzyloxy)-2-chloro-6a-ethyl-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-6(5H)-one and (6aS,8R)-8-(benzyloxy)-2-chloro-6a-ethyl-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-6(5H)-one

[0274] To tert-butyl (2R,4R)-4-(benzyloxy)-2-((4-bromo-6-chloropyridazin-3-yl)carbamoyl)-2-ethylpyrrolidine-1-carboxylate (473 mg, 0.88 mmol) in DCM (17 mL) was added TFA (17 mL, 222 mmol). The reaction was stirred at room temperature for 3 hours and then concentrated. The residue was dissolved in MeCN (15 mL). N,N-Diisopropylethylamine (0.76 mL, 4.38 mmol) was added and the reaction was stirred at 80° C. for 2 hours and then allowed to cool to room temperature overnight. The reaction was concentrated to give crude (6aR,8R)-8-(benzyloxy)-2-chloro-6a-ethyl-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-6(5H)-one (Intermediate 8, estimated quantitative yield), which was used directly without further purification. The other diastereomer was synthesized using the same procedure. Note: (6aR,8R)-8-(benzyloxy)-2-chloro-6a-ethyl-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-6(5H)-one can be purified via SiO2 FCC (0:20:80 to 60:20:40 EtOAc / DCM / hexanes). 18 H 20 ClN4O2[M+H] + LCMS calculated for: m / z=359.1, found: 359.1.

[0275] Intermediate 9: (6aR,8S)-2-chloro-6a-ethyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol [ka]

[0276] Step 1: (6aR,8R)-8-(benzyloxy)-2-chloro-6a-ethyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine [ka]

[0277] To a solution of (6aR,8R)-8-(benzyloxy)-2-chloro-6a-ethyl-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-6(5H)-one (1.9 g, 5.3 mmol, Intermediate 8a) in THF (25 mL) at 0 °C was added BH3·Me2S (2 M in THF, 5 mL, 10 mmol). The reaction mixture was stirred at 55 °C for approximately 48 h, after which additional BH3·Me2S (2 M in THF, 2.5 mL, 5 mmol) was added. The reaction was stirred at 55 °C for 3 h, then cooled, quenched with MeOH, and concentrated. The residue was dissolved in EtOH (40 mL), then cooled to 0 °C and treated with AcOH (6.3 mL, 105 mmol) followed by two portions of NaBHCN (0.8 g, 12.7 mmol). The reaction was warmed to room temperature and then stirred at 70 °C for 6 h, after which it was cooled to room temperature and concentrated. The residue was diluted with DCM and saturated NaHCO (aq) and extracted with DCM (3x). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude material was purified via SiOFCC (0-20% MeOH in DCM) to give (6aR,8R)-8-(benzyloxy)-2-chloro-6a-ethyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine (1.22 g, 60%). 18 H 22 ClNO[M+H] + LCMS calculated for: m / z=345.1, found: 345.0.

[0278] Step 2: (6aR,8R)-2-chloro-6a-ethyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol [ka]

[0279] To (6aR,8R)-8-(benzyloxy)-2-chloro-6a-ethyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine (1.2 g, 3.5 mmol) in DCM (35 mL) at 0 °C was added BCl3 (1 M in DCM, 10 mL, 10 mmol). The reaction was stirred at 0 °C for 1.5 h and then slowly quenched with saturated NaHCO3 (aq). The mixture was poured into water, neutralized with additional saturated NaHCO3 (aq), and then extracted with DCM (3x). The combined organic layers were washed with brine (1x), dried over MgSO4, filtered, and concentrated. The residue was taken up in MTBE, then sonicated and filtered to give (6aR,8R)-2-chloro-6a-ethyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol (740 mg, 84%) as a white solid. 11 H 16 ClNO[M+H] + LCMS calculated for: m / z=255.1, found: 255.0.

[0280] Step 3: (6aR,8S)-2-chloro-6a-ethyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl 4-nitrobenzoate [ka]

[0281] To a mixture of (6aR,8R)-2-chloro-6a-ethyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol (200 mg, 0.79 mmol), 4-nitrobenzoic acid (262 mg, 1.57 mmol), and polymer-supported PPh3 (100-200 mesh, approximately 1.6 mmol / g loading, 735 mg, 1.18 mmol) in THF (10 mL) was added diisopropyl azodicarboxylate (0.23 mL, 1.18 mmol). The reaction was stirred at 65 °C for 25 min and then allowed to cool to room temperature. The mixture was filtered, and the resulting filtrate was purified via SiOFCC (0-10% MeOH in DCM) to give (6aR,8S)-2-chloro-6a-ethyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl 4-nitrobenzoate (estimated quantitative yield) as a yellow solid. 18 H 19 ClNO4[M+H] + LCMS calculated for: m / z=404.1, found: 404.0.

[0282] Step 4: (6aR,8S)-2-chloro-6a-ethyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol

[0283] To (6aR,8S)-2-chloro-6a-ethyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl 4-nitrobenzoate (1.16 g, 2.86 mmol) in MeOH (8 mL) and THF (16 mL) was added NaOH (802 mg, 1.18 mmol) in water (9 mL). The reaction was stirred at room temperature for 15 minutes, then diluted with a small amount of water, followed by bulk extraction with DCM (3x). The combined organic layers were washed with brine (1x), then dried over MgSO4, filtered, and concentrated. The residue was taken up in MTBE, and the resulting mixture was filtered through a 0.45 μm PTFE frit filter. The collected solid was washed with MTBE and dried to give the title compound (Intermediate 9, 548 mg, 75%) as a white solid. 11 H 16 ClNO[M+H] + LCMS calculated for: m / z=255.1, found: 255.0. Intermediate 10: (6aR,8S)-6a-ethyl-2-(3-fluoro-2-methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol [ka]

[0284] Step 1. (6aR,8R)-8-(benzyloxy)-6a-ethyl-2-(3-fluoro-2-methoxyphenyl)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-6(5H)-one [ka]

[0285] A mixture of (6aR,8R)-8-(benzyloxy)-2-chloro-6a-ethyl-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-6(5H)-one (1.1 g, 3.0 mmol, Intermediate 8a), 3-fluoro-2-methoxyphenylboronic acid (1.3 g, 7.6 mmol), dichloro-1,1'-bisdiphenylphosphino)ferrocene palladium(II) dichloromethane (744 mg, 0.9 mmol), and potassium carbonate (2.1 g, 15.2 mmol) in dioxane (25.0 mL) and water (7.0 mL) was sparged with N for approximately 5 minutes. The reaction was stirred at 100 °C and monitored by LCMS. After 3 h, the reaction was resubjected to equal amounts of all reagents, sparged with N2 for 5 min, and then resumed heating at 100 °C for an additional 1 h. The reaction was then cooled to room temperature and poured into water. It was extracted with EtOAc (3x), then dried over MgSO4, filtered, and concentrated. The crude material was purified via SiO2 FCC: 0-100% EtOAc / hexanes to afford the title compound (1.11 g, 82% yield) as an orange foam. 25 H 26 FN4O3[M+H] + LCMS calculated for: m / z=449.2, found: 449.1.

[0286] Step 2. (6aR,8R)-8-(benzyloxy)-6a-ethyl-2-(3-fluoro-2-methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine [ka]

[0287] To (6aR,8R)-8-(benzyloxy)-6a-ethyl-2-(3-fluoro-2-methoxyphenyl)-6a,7,8,9-tetrahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-6(5H)-one (393 mg, 0.88 mmol) in THF (5.00 mL) was added lithium aluminum hydride (1 M in THF, 5.3 mL, 5.3 mmol) dropwise at 0 °C. The reaction was allowed to warm to ambient temperature. After 2 h, additional lithium aluminum hydride (1.50 mL, 1.50 mmol) was added. After 1 h, the reaction was cooled to 0 °C, then methanol (8.0 mL) was added dropwise, followed by acetic acid (1.5 mL, 26.3 mmol). The reaction was allowed to warm to ambient temperature, then sodium cyanoborohydride (551 mg, 8.8 mmol) was added and stirred at 80 °C overnight. The reaction was then neutralized with saturated NaHCO (aq) and then poured into water and extracted with EtOAc (3x). The combined organic layers were washed with brine (1x), dried over MgSO, filtered, and concentrated. Purification via SiOFCC: 0-10% MeOH / DCM afforded the title compound (347 mg, 91% yield) as a beige solid. 25 H 28 FN4O2[M+H] + LCMS calculated for: m / z=435.2, found: 435.1.

[0288] Step 3. (6aR,8R)-6a-Ethyl-2-(3-fluoro-2-methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo-[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol [ka]

[0289] To (6aR,8R)-8-(benzyloxy)-6a-ethyl-2-(3-fluoro-2-methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine (961 mg, 2.21 mmol) in DCM (25.0 mL) was added trichloroborane (6.63 mL, 6.63 mmol) slowly (to the bottom of the flask) at -78 °C. After complete addition, the reaction was stirred for approximately 2 minutes and then warmed to 0 °C (ice-water bath). After 20 minutes, the reaction was quenched by the dropwise addition of water at 0 °C, neutralized with saturated NaHCO (aq), and then extracted with DCM (3x). The DCM layers were combined, dried over MgSO, filtered, and concentrated. The crude was purified via SiOFCC: 0-20% MeOH / DCM to give the title compound (551 mg, 72%). 18 H 22 FN4O2[M+H] + LCMS calculated for: m / z=345.2, found: 345.1.

[0290] Step 4. (6aR,8S)-6a-Ethyl-2-(3-fluoro-2-methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol

[0291] To a briefly sonicated mixture of 4-nitrobenzoic acid (485 mg, 2.90 mmol), (6aR,8R)-6a-ethyl-2-(3-fluoro-2-methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol (500 mg, 1.45 mmol), and triphenylphosphine (2.72 g, 4.36 mmol, 1.6 mmol / g polymer-bound) in THF (20 mL) was added diisopropyl azodicarboxylate (858 μL, 4.36 mmol). The mixture was stirred at 65 °C and monitored by LC-MS. After 1.5 h, the reaction was cooled, filtered to remove triphenylphosphine, and rinsed with THF (20 mL) followed by methanol (40 mL). To the filtrate was added potassium carbonate (815 mg, 5.90 mmol) and the suspension was allowed to stir for 2 hours. The reaction was diluted with DCM and saturated sodium bicarbonate (aq). The organic layer was separated and the aqueous layer was extracted once with DCM and then once with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The crude material was purified over SiO2 (0-20% MeOH / DCM) to give the desired product as a white solid (330 mg, 66% yield). 18 H 22 FN4O2[M+H] + LCMS calculated for: m / z=345.2, found: 345.0. Intermediate 11: (6aS,8S)-6a-ethyl-2-(3-fluoro-2-methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol [ka]

[0292] The title compound was prepared starting from intermediate 8b according to the procedure used for intermediate 10. 18 H 22 FN4O2[M+H] + LCMS calculated for: m / z=345.2, found: 345.0. Intermediate 12: (6aR,8S)-2-chloro-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol [ka]

[0293] Step 1. (2R,4S)-4-(benzyloxy)-N-(4-bromo-6-chloropyridazin-3-yl)-2-methylpyrrolidine-2-carboxamide [ka]

[0294] To a cold solution of (6S,7aR)-6-(benzyloxy)-7a-methyltetrahydro-1H,3H-pyrrolo[1,2-c]oxazole-1,3-dione (12.0 g, 45.9 mmol, prepared by a procedure similar to that described in Example 55) and 4-bromo-6-chloropyridazin-3-amine (8.6 g, 41.3 mmol) in THF (60.0 mL) was added NaH (60% in mineral oil, 2.76 g, 68.9 mmol) in several portions. The reaction was allowed to stir until no starting material was consumed. Another portion of 60% NaH (0.5 equivalents) was then added, and HPLC showed a significant improvement in conversion. The reaction mixture was quenched with 10% citric acid solution (100 mL) and extracted with a mixture of chloroform and IPA (3:1, 75 mL × 5), and the combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness to give the title compound (19.5 g), which was used in the next reaction without further purification. 17 H 19 BrClN4O2[M+H] + LCMS calculated for: m / z=427.03, found: 427.2.

[0295] Step 2. (6aR,8S)-8-(benzyloxy)-2-chloro-6a-methyl-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-6(5H)-one [ka]

[0296] To a solution of (2R,4S)-4-(benzyloxy)-N-(4-bromo-6-chloropyridazin-3-yl)-2-methyl-pyrrolidine-2-carboxamide (19.5 g, 45.9 mmol) in THF (100 mL) was added Na2CO3 (19.5 g, 184 mmol) and stirred at ambient temperature for 12 hours. The reaction mixture was condensed and diluted with 100 mL of heptane. The solid was filtered and washed with water to give a white solid. The solid was taken up in DCM and saturated Na2CO3 (aq) and then separated. The aqueous layer was re-extracted with DCM (3x). The organic layers were combined, filtered through a layer of silica gel, and condensed to give the title compound (8.5 g, 54% yield). The crude material was carried on to the next step without further purification. C 17 H 18 ClN4O2[M+H] + LCMS calculated for: m / z=345.1, found: 345.5.

[0297] Step 3. (6aR,8S)-8-(benzyloxy)-2-chloro-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine [ka]

[0298] To a solution of (6aR,8S)-8-(benzyloxy)-2-chloro-6a-methyl-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-6(5H)-one (8.20 g, 23.0 mmol) in dry THF (60.0 mL) was added BH₃·DMS (18.1 mL, 191 mmol) at 0 °C. The reaction was warmed to room temperature and stirred at 50 °C for 90 min. Upon completion by LCMS, the reaction was cooled to 0 °C and quenched by the dropwise addition of methanol. The reaction was condensed and then taken up in EtOH (60 mL). To this solution was added NaBH₃CN (11.9 g, 191 mmol) and acetic acid (21.8 mL, 381 mmol) at 0 °C. The reaction was slowly heated to 80 °C and stirred overnight. The reaction was cooled to room temperature, poured into saturated NaHCO3 (aq) and extracted with DCM (3x). The combined organic phases were dried over Na2SO4 and filtered. The residue was purified by SiO2 FCC 10-60% DCM / (1% MeOH in EtOAc) to give the title compound (5.3 g, 6% yield) as a colorless solid. 17 H 20 ClNO[M+H] + LCMS calculated for: m / z=331.1, found: 331.5.

[0299] Step 4: (6aR,8S)-2-chloro-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol

[0300] Trichloroborane (1 M in DCM, 3.05 mL, 3.05 mmol) was added dropwise to a solution of (6aR,8S)-8-(benzyloxy)-2-chloro-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine (202 mg, 0.61 mmol) in DCM (3.00 mL) at −78 °C. The resulting mixture was stirred at −78 °C for 30 min and quenched with MeOH (10 mL). The volatiles were evaporated, and the residue was basified by adding 10% Na2CO3 solution and then extracted with CHCl3 / IPA (3:1, 10 mL × 6). The combined organic phase was dried over Na2SO4, filtered, and concentrated. The residue was dried under high vacuum to give the title compound (140 mg, 95% yield) as a white solid. The crude material was carried on to the next step without further purification. 10 H 14 ClNO[M+H] + LCMS calculated for: m / z=241.1, found: 241.3. Intermediate 13: (6aS,8S)-2-chloro-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol [ka]

[0301] Step 1: (6aS,8S)-2-chloro-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol

[0302] The title compound was synthesized according to the procedure described for Intermediate 12. 10 H 14 ClNO[M+H] + LCMS calculated for: m / z=241.1, found: 241.2. Intermediate 14: (6aS,8R)-2-chloro-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol [ka]

[0303] The title compound was synthesized according to the procedure described for Intermediate 12 using "Diastereomer B" from Example 55, Step 5. 10 H 14 ClNO[M+H] + LCMS calculated for: m / z=241.1, found: 241.2. Intermediate 15: (6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol [ka]

[0304] A mixture of (6aS,8R)-2-chloro-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol (Intermediate 14) (200 mg, 0.83 mmol), 3-fluoro-2-hydroxyphenylboronic acid (518 mg, 3.32 mmol), KPO (1.06 g, 4.99 mmol), and XPhos Pd G (65 mg, 0.08 mmol) in 1,4-dioxane (6.00 mL) and water (0.30 mL) was purged with N for 2 minutes. The reaction was stirred at 100 °C overnight. The reaction was poured into saturated NaHCO (aqueous) solution and extracted with CHCl / IPA (3:1, 5x). The combined organic phase was dried over Na2SO4. After removal of the solvent, the residue was purified by SiO2FCC 0-10% MeOH in DCM to give the title compound (160 mg, 61% yield) as a yellow solid. 16 H 18 FN4O 2[ M+H] + LCMS calculated for: m / z=317.1, found: 317.5. Intermediate 16: 5-(trifluoromethyl)-6-vinylpyridin-3-ol [ka]

[0305] To a vial was added 6-chloro-5-(trifluoromethyl)-3-pyridinol (500 mg, 2.53 mmol), cesium carbonate (1.51 g, 4.56 mmol), potassium vinyltrifluoroborate (610 mg, 4.56 mmol), followed by 1,4-dioxane (7.23 mL) and water (1.21 mL). The mixture was sparged with N for 5 minutes, then SPhos Pd G (220 mg, 0.31 mmol) was added. The reaction was sealed with a septa cap, purged with N for another 5 minutes, and then stirred at 95 °C. After 5 hours, the reaction was cooled to room temperature, filtered through Celite, condensed, and then purified using SiOFCC 0-20% MeOH in DCM to give the title compound (280 mg, 59% yield). CHFNO [M+H] + LCMS calculated for: m / z=190.1, found: 190.0. Intermediate 17: 6-Fluoro-4-iodonicotinic acid [ka]

[0306] To a solution of 6-fluoronicotinic acid (1.0 g, 7.09 mmol) in THF (14.0 mL) was added LDA (8.9 mL, 17.7 mmol) dropwise at −78° C. The reaction was stirred at −78° C. for 10 minutes and then at −50° C. for 90 minutes. The reaction was returned to −78° C., and iodine (1.80 g, 7.09 mmol) in 4.0 mL of THF was added dropwise, and the reaction was stirred at −50° C. for 1 hour, then quenched by adding acetic acid (2.84 mL, 49.6 mmol) in 3.0 mL of THF at −78° C. The resulting mixture was poured into 10% citric acid solution and extracted with EtOAc (3×). The combined organic phase was dried over Na2SO4, filtered, and concentrated. The crude material was purified by preparative HPLC on a C18 column (30 x 250 mm, 10 μM) using a mobile phase of 8-55% MeCN / HO (containing 0.1% TFA) (tR = 18 min). The desired fractions were collected and extracted with EtOAc (3x). The organic phase was dried over Na2SO4, filtered, and concentrated to give the title compound (505 mg, 27% yield). CH4FINO2 [M+H] + LCMS calculated for: m / z=267.9, found: 268.2. Intermediate 18: 5-Fluoro-6-vinylpyridin-3-ol [ka]

[0307] A mixture of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (500 μL, 2.95 mmol), potassium carbonate (1.42 g, 10.3 mmol), 6-chloro-5-fluoropyridin-3-ol (300 mg, 2.03 mmol), and XPhos Pd G2 (80.0 mg, 0.10 mmol) in 1,4-dioxane (15.8 mL) and water (3.20 mL) was sparged with N2 for approximately 10 minutes and then stirred at 80 °C overnight. The reaction was allowed to cool to room temperature and then filtered through Celite and rinsed with MeOH. The filtrate was concentrated, dissolved in DCM, and purified via SiO2 FCC: 0-100% EtOAc / hexanes to give the title compound (300 mg, quantitative yield) as a yellow oil. C7H7FNO[M+H]+ LCMS calculated for: m / z=140.1, found: 139.9. Intermediate 19: 5-Hydroxy-3,6-dimethylpicolinonitrile [ka]

[0308] Step 1. 6-Bromo-2,5-dimethylpyridin-3-ol [ka]

[0309] 6-Bromo-2,5-dimethylpyridin-3-amine (1.0 g, 4.97 mmol) was dissolved in water (9.0 mL) and sulfuric acid (2.5 mL, 4.97 mmol). The solution was cooled to 0 °C, and sodium nitrite (686 mg, 9.95 mmol) was added portionwise over 10 min. The solution was stirred at room temperature for 5 min, then at 90 °C for 1–2 h, or until complete consumption of the starting material was confirmed by LCMS. The reaction mixture was cooled to room temperature and carefully neutralized with saturated NaHCO (aq) to a pH of approximately 7–8. The aqueous layer was washed with brine and extracted with EtOAc (4×). The combined organic layers were dried over NaSO and concentrated to dryness to give the title compound (850 mg, 72% yield). The crude material was carried on to the next step without further purification. C7H9BrNO[M+H] + LCMS calculated for m / z = 202.0, found: 202.1.

[0310] Step 2. 5-Hydroxy-3,6-dimethylpicolinonitrile

[0311] 6-Bromo-2,5-dimethylpyridin-3-ol (720 mg, 3.56 mmol) and copper(I) cyanide (638 mg, 7.13 mmol) were dissolved in DMF (11.8 mL), and the resulting mixture was degassed by sparging with nitrogen. The mixture was heated at 130 °C for 3 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with brine. The aqueous layer was re-extracted twice with EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated to dryness. The crude mixture was dissolved in DMSO and centrifuged to remove any undissolved solids. The crude mixture was then purified by reverse-phase preparative HPLC 10-30% ACN / water (containing 0.1% TFA) to give the title compound (407 mg, 77% yield). C8H9N2O [M+H] + LCMS calculated for: m / z=149.1, found: 149.2. Example 1: 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexa-hydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)benzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0312] Step 1: (6aR,8R)-2-chloro-8-(4-formylphenoxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl ester [ka]

[0313] To tert-butyl (6aR,8S)-2-chloro-8-hydroxy-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (200 mg, 0.610 mmol, Intermediate 1), polymer-supported triphenylphosphine (0.760 g, 1.22 mmol, 100-200 mesh with 1.6 mmol PPh / g loading), and 4-hydroxybenzaldehyde (299 mg, 2.45 mmol) in THF (7.00 mL) was added diisopropyl azodicarboxylate (181 µL, 0.920 mmol). The solution was stirred at 80 °C for 0.5 h, then cooled to room temperature, filtered, and concentrated under reduced pressure. The crude material was purified via SiO2 FCC: 0-100% EtOAc / Hexanes to afford tert-butyl (6aR,8R)-2-chloro-8-(4-formylphenoxy)-6a,7,8,9 tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (172 mg, 65%) as an off-white foam. 21 H 24 ClN4O4[M+H] + LCMS calculated for: m / z=431.2, found: 431.1.

[0314] Step 2: (6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-8-(4-formylphenoxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl ester [ka]

[0315] To crude (6aR,8R)-2-chloro-8-(4-formylphenoxy)-6a,7,8,9-tetrahydropyrrolo-[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (19.8 mg, 50.0 μmol) in THF (1.00 mL) and water (200 μL) was added dichloro-1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane (11.3 mg, 10.0 μmol), (3,5-difluoro-2-hydroxyphenyl)boronic acid (24.0 mg, 140 μmol), and potassium carbonate (31.8 mg, 230 μmol). The solution was sparged with N for approximately 2 minutes and then stirred at 100°C. After 1 h, the reaction was cooled to room temperature, concentrated under reduced pressure, and purified via SiO2 FCC: 0-100% EtOAc / hexanes to afford tert-butyl (6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-8-(4-formylphenoxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino-[2,3-c]pyridazine-5(6H)-carboxylate (10.0 mg, 41%) as a yellow film. 27 H 27 F2N4O5[M+H] + LCMS calculated for: m / z=525.2, found: 525.0.

[0316] Step 3: 4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)benzaldehyde [ka]

[0317] To tert-butyl (6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-8-(4-formylphenoxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (10.0 mg, 20.0 μmol) in DCM (2.00 mL) was added 2,2,2-trifluoroacetic acid (150 μL, 1.96 mmol). The solution was stirred at room temperature for 1.5 hours and concentrated under reduced pressure to give 4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino-[2,3-c]pyridazin-8-yl)oxy)benzaldehyde (10.3 mg, quantitative) as the TFA salt. 22 H 19 F2N4O3[M+H] + LCMS calculated for: m / z=425.1, found: 425.2.

[0318] Step 4: 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)benzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0319] To 4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)benzaldehyde trifluoroacetate (10.3 mg, 20.0 μmol) and 3-(3-oxo-5-piperazin-1-yl-1H-isoindol-2-yl)piperidine-2,6-dione (12.4 mg, 30.0 μmol, Intermediate 2) in NMP (1.00 mL) was added acetic acid (5.50 μL, 100 μmol). The reaction was sonicated and stirred at 50° C. for 1 hour, then sodium triacetoxyborohydride (13.0 mg, 60.0 μmol) was added. The solution was stirred at 50 °C for 20 minutes, then at 70 °C for 1.5 hours. The reaction was cooled to room temperature, filtered, and purified directly via preparative LCMS (7.8-25.8% CHCN in HO with 0.1% TFA) to afford 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)benzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.50 mg, 2.7% yield) as a white TFA salt. 39 H 39 F2N8O5[M+H] + LCMS calculated for: m / z=737.3, found: 737.2.

[0320] Examples 2 to 25 Examples 2-25 shown below in Table 1 were prepared as TFA salts by the method used to prepare Example 1, utilizing the appropriate starting materials and intermediates. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] Example 26: 3-(6-(4-((2-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexa-hydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)thio)pyrimidin-5-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0321] Step 1: (6aR,8S)-2-(3,5-difluoro-2-methoxyphenyl)-8-hydroxy-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl ester [ka]

[0322] The title compound was prepared using a procedure similar to that described for Example 1, Step 2, using Intermediate 1 instead of tert-butyl (6aR,8R)-2-chloro-8-(4-formyl-phenoxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate, and (3,5-difluoro-2-methoxyphenyl)boronic acid instead of (3,5-difluoro-2-hydroxyphenyl)boronic acid. 21 H 25 F2N4O4[M+H] + LCMS calculated for: m / z=435.2, found: 435.1.

[0323] Step 2: (6aR,8S)-tert-butyl 2-(3,5-difluoro-2-methoxyphenyl)-8-((methylsulfonyl)oxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate [ka]

[0324] To a mixture of tert-butyl (6aR,8S)-2-(3,5-difluoro-2-methoxyphenyl)-8-hydroxy-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (93.3 mg, 215 μmol) and triethylamine (89.8 μL, 644 μmol) in THF (4.00 mL) was added methanesulfonyl chloride (24.9 μL, 32.2 μmol). The reaction mixture was stirred overnight. LCMS analysis indicated an incomplete reaction, and additional triethylamine (479 μL, 3.44 mmol) and methanesulfonyl chloride (249 μL, 3.22 mmol) were added. The reaction was concentrated under reduced pressure and purified via SiO2 FCC: 0-100% EtOAc / hexanes to afford tert-butyl (6aR,8S)-2-(3,5-difluoro-2-methoxyphenyl)-8-((methylsulfonyl)oxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (110 mg, quantitative yield) as a white solid. 22 H 27 F2N4O6S[M+H] + LCMS calculated for: m / z=513.2, found: 513.1.

[0325] Step 3: (6aR,8R)-2-(3,5-difluoro-2-methoxyphenyl)-8-((5-formylpyrimidin-2-yl)thio)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl ester [ka]

[0326] A mixture of tert-butyl (6aR,8S)-2-(3,5-difluoro-2-methoxyphenyl)-8-((methyl-sulfonyl)oxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (44.0 mg, 85.8 μmol), 2-sulfanylpyrimidine-5-carbaldehyde (24.1 mg, 172 μmol), and potassium carbonate (23.7 mg, 172 μmol) in MeCN (1.00 mL) was stirred at 90° C. for 24 hours. The reaction was cooled to room temperature, diluted with EtOAc, filtered, and concentrated under reduced pressure. The crude material was purified via SiO2 FCC: 0-100% EtOAc / Hexanes to afford tert-butyl (6aR,8R)-2-(3,5-difluoro-2-methoxyphenyl)-8-((5-formylpyrimidin-2-yl)thio)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (21.8 mg, 46% yield) as a white film. 26 H 27 F2N6O4S[M+H] + LCMS calculated for: m / z=557.2, found: 557.1.

[0327] Step 4: 2-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)thio)pyrimidine-5-carbaldehyde [ka]

[0328] Boron tribromide (1.18 mL, 1.18 mmol) was added to a solution of tert-butyl (6aR,8R)-2-(3,5-difluoro-2-methoxyphenyl)-8-((5-formylpyrimidin-2-yl)thio)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (21.8 mg, 39.2 μmol) in DCM (2.00 mL). The reaction was stirred at room temperature for 48 hours. The reaction mixture was carefully poured into a saturated aqueous solution of NaHCO3, and the aqueous phase was extracted with DCM. The combined organics were washed with saturated brine solution, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (10.6 mg, 61% yield) as a pale yellow solid. C 20 H 17 F2N6O2S[M+H] + LCMS calculated for: m / z=443.1, found: 442.9.

[0329] Step 5: 3-(6-(4-((2-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)thio)pyrimidin-5-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0330] Sodium cyanoborohydride (4.52 mg, 71.9 μmol) was added to a solution of 2-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)thio)pyrimidine-5-carbaldehyde (10.6 mg, 24.0 μmol), 3-(3-oxo-5-piperazin-1-yl-1H-isoindol-2-yl)piperidine-2,6-dione (15.7 mg, 47.9 μmol, Intermediate 2), and acetic acid (6.90 μL, 121 μmol) in MeOH (1.00 mL). The reaction was stirred at 80° C. for 4 hours. The reaction mixture was cooled to room temperature, diluted with MeOH, and filtered. The filtrate was directly purified via preparative HPLC (Waters CSH-C18, 5 μM, 30 × 100 mm, 6.5–24.5% MeCN / water (containing 0.1% TFA) over 5 min) to afford the TFA salt of the title compound (1.2 mg, 5.1% yield) as a white solid. 37 H 37 F2N 10 O4S[M+H] + LCMS calculated for: m / z=755.3, found: 755.2. Example 27: 3-(6-(4-((6-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0331] Step 1: 4-Methyl-5-vinylpyridin-2-ol [ka]

[0332] A solution of 5-bromo-4-methylpyridin-2-ol (150 mg, 798 μmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (338 μL, 1.99 mmol), potassium carbonate (441 mg, 3.19 mmol), and dichloro-1,1′-bisdiphenylphosphino)ferrocene palladium(II) dichloromethane (196 mg, 239 μmol) in a mixture of 1,4-dioxane (4.00 mL) and water (1.00 mL) was sparged with nitrogen for 5 minutes. The reaction was heated at 100° C. for 1 hour. The reaction was cooled to room temperature, quenched with saturated aqueous NH4Cl (1.00 mL), filtered, and concentrated under reduced pressure. The crude material was purified via SiOFCC: 0-5% MeOH / DCM to give 4-methyl-5-vinylpyridin-2-ol (108 mg, quantitative yield). 10 NO[M+H] + LCMS calculated for: m / z=136.1, found: 136.0.

[0333] Step 2: (6aR,8R)-2-chloro-8-((4-methyl-5-vinylpyridin-2-yl)oxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl ester [ka]

[0334] Diisopropyl azodicarboxylate (169 μL, 857 μmol) was added to a solution of tert-butyl (6aR,8S)-2-chloro-8-hydroxy-6a,7,8,9-tetrahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (70.0 mg, 214 μmol, Intermediate 1), 4-methyl-5-vinylpyridin-2-ol (107 mg, 793 μL), and triphenylphosphine (225 mg, 857 μL) in THF (2.00 mL), and the reaction mixture was heated at 60° C. for 30 minutes. The reaction was cooled to room temperature and directly purified via SiOFCC: 0-100% EtOAc / hexanes to afford tert-butyl (6aR,8R)-2-chloro-8-((4-methyl-5-vinylpyridin-2-yl)oxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (95.1 mg, quantitative yield). 22 H 27 ClNO3[M+H] + LCMS calculated for: m / z=444.2 / 446.2, found: 444.1 / 446.2.

[0335] Step 3: (6aR,8R)-2-chloro-8-((5-formyl-4-methylpyridin-2-yl)oxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl ester [ka]

[0336] Osmium tetroxide (49.0 μL, 153 μmol) was added to a solution of tert-butyl (6aR,8R)-2-chloro-8-((4-methyl-5-vinylpyridin-2-yl)oxy)-6a,7,8,9-tetrahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (68.0 mg, 153 μmol) and sodium periodate (98.3 mg, 460 μmol) in a mixture of THF (4.00 mL) and water (1.00 mL). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with DCM. The combined organic layers were washed with saturated brine solution, dried over MgSO4, filtered, and concentrated under reduced pressure to give crude tert-butyl (6aR,8R)-2-chloro-8-((5-formyl-4-methylpyridin-2-yl)oxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (68 mg, quantitative yield). The material was used in the next step without further purification. 21 H 25 ClNO4[M+H] + LCMS calculated for: m / z=446.2, found: 446.1.

[0337] Step 4: (6aR,8R)-2-(3,5-difluoro-2-methoxyphenyl)-8-((5-formyl-4-methylpyridin-2-yl)oxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl ester [ka]

[0338] The title compound was prepared using a procedure similar to that described in Example 1, Step 2, using (6aR,8R)-2-chloro-8-((5-formyl-4-methylpyridin-2-yl)oxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl instead of (6aR,8R)-2-chloro-8-(4-formylphenoxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl, and (3,5-difluoro-2-methoxyphenyl)boronic acid instead of (3,5-difluoro-2-hydroxyphenyl)boronic acid. 28 H 30 F2N5O5[M+H] + LCMS calculated for: m / z=554.2, found: 554.2.

[0339] Step 5: (6aR,8R)-2-(3,5-difluoro-2-methoxyphenyl)-8-((5-(hydroxymethyl)-4-methylpyridin-2-yl)oxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl ester [ka]

[0340] Sodium borohydride (21.0 mg, 555 μL) was added to a solution of tert-butyl (6aR,8R)-2-(3,5-difluoro-2-methoxyphenyl)-8-((5-formyl-4-methylpyridin-2-yl)oxy)-6a,7,8,9-tetrahydro-pyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (119 mg, 214 μL) in a mixture of MeOH (1.00 mL) and THF (1.00 mL). The reaction was stirred at room temperature for 30 minutes. The reaction was quenched with saturated aqueous NH4Cl and extracted with DCM. The combined organics were washed with saturated brine solution, dried over MgSO4, filtered, and concentrated under reduced pressure to give crude (6aR,8R)-2-(3,5-difluoro-2-methoxyphenyl)-8-((5-(hydroxymethyl)-4-methylpyridin-2-yl)oxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl (119 mg, quantitative yield). The material was used in the next step without further purification. C 28 H 32 F2N5O5[M+H] + LCMS calculated for: m / z=556.2, found: 556.2.

[0341] Step 6: (6aR,8R)-tert-butyl 8-((5-(chloromethyl)-4-methylpyridin-2-yl)oxy)-2-(3,5-difluoro-2-methoxyphenyl)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate [ka]

[0342] The title compound was prepared using a procedure similar to that described for Example 26, Step 2, using crude (6aR,8R)-2-(3,5-difluoro-2-methoxyphenyl)-8-((5-(hydroxymethyl)-4-methylpyridin-2-yl)oxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl instead of (6aR,8S)-2-(3,5-difluoro-2-methoxyphenyl)-8-hydroxy-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl. 28 H 31 ClF2N5O4[M+H] + LCMS calculated for: m / z=574.2 / 576.2, found: 574.2 / 576.1.

[0343] Step 7: (6aR,8R)-2-(3,5-difluoro-2-methoxyphenyl)-8-((5-((4-(2-(2,6-dioxo-piperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)methyl)-4-methylpyridin-2-yl)oxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl ester [ka]

[0344] A solution of tert-butyl (6aR,8R)-8-((5-(chloromethyl)-4-methylpyridin-2-yl)oxy)-2-(3,5-difluoro-2-methoxyphenyl)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (11.9 mg, 20.7 μmol) and 3-(3-oxo-5-piperazin-1-yl-1H-isoindol-2-yl)piperidine-2,6-dione (7.90 mg, 24.1 μmol, Intermediate 2) in THF (1.00 mL) was sonicated until a homogeneous suspension was formed. N,N-Diisopropylethylamine (7.94 μL, 45.6 μmol) and MeCN (1.00 mL) were added, and the reaction was stirred at 120 °C for 2 h. The reaction was cooled to room temperature and concentrated under reduced pressure to give crude (6aR,8R)-2-(3,5-difluoro-2-methoxyphenyl)-8-((5-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)methyl)-4-methylpyridin-2-yl)oxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl. 45 H 50 F2N9O7[M+H] + LCMS calculated for: m / z=866.4, found: 866.4.

[0345] Step 8: 3-(6-(4-((6-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0346] The title compound was prepared by the reaction of (6aR,8R)-2-(3,5-difluoro-2-methoxyphenyl)-8-((5-formylpyrimidin-2-yl)thio)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate with tert-butyl ether. Prepared using a procedure similar to that described for Example 26, Step 4, using tert-butyl (2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)methyl)-4-methylpyridin-2-yl)oxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate. 39 H 40 F2N9O5[M+H] + LCMS calculated for: m / z=752.3, found: 752.3.

[0347] Examples 28 to 31 Examples 28-31 shown below in Table 2 were prepared as TFA salts by the method used to prepare Example 27, utilizing the appropriate starting materials and intermediates. [Table 2-1] [Table 2-2] [Table 2-3] Example 32: 3-(6-(4-((6-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0348] The title compound was prepared using procedures similar to those described in Example 26, Steps 2-3 and Example 1, Steps 2-4, using the appropriate starting materials and intermediates. 39 H 39 F2N8O4S[M+H] + LCMS calculated for: m / z=753.3, found: 753.2. Example 33: 3-(6-(4-((6-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0349] The title compound was prepared using procedures similar to those described for Example 27, Steps 2-3 and Example 1, Steps 2-4, using the appropriate starting materials and intermediates. 38 H 38 F2N9O5[M+H] + LCMS calculated for: m / z=738.3, found: 738.2. Example 34: 3-(6-(4-(((3R,5S)-4-((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[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 [ka]

[0350] Step 1: (6aR,8S)-2-chloro-8-((methylsulfonyl)oxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]-pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl ester [ka]

[0351] The title compound was prepared using a procedure similar to that described for Example 26, Step 2, using (6aR,8S)-2-chloro-8-hydroxy-6a,7,8,9-tetrahydropyrrolo-[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl (6aR,8S)-2-(3,5-difluoro-2-methoxyphenyl) ...chloro-8-hydroxy-6a,7,8,9-tetrahydropyrrolo-[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl (Intermediate 1). 15 H 22 ClN4O5S[M+H] + LCMS calculated for: m / z=405.1, found: 405.0.

[0352] Step 2: (6aR,8R)-2-chloro-8-cyano-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl ester [ka]

[0353] A mixture of tert-butyl (6aR,8S)-2-chloro-8-((methylsulfonyl)oxy)-6a,7,8,9-tetrahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (265 mg, 655 μL) and sodium cyanide (96.2 mg, 1.96 mmol) in DMSO (500 μL) was stirred at 80° C. overnight. The mixture was cooled to room temperature, diluted with DCM, and washed with water. The organics were dried over MgSO, filtered, and concentrated under reduced pressure. The crude material was purified via SiOFCC: 0-100% EtOAC / hexanes to give tert-butyl (6aR,8R)-2-chloro-8-cyano-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (150 mg, 72% yield). 15 H 19 ClNO2[M+H] + LCMS calculated for: m / z=336.1, found: 336.1.

[0354] Step 3: (6aR,8R)-8-cyano-2-(3-fluoro-2-hydroxyphenyl)-6a,7,8,9-tetrahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl ester [ka]

[0355] The title compound was prepared using a procedure similar to that described for Example 1, Step 2, using (6aR,8R)-2-chloro-8-cyano-6a,7,8,9-tetrahydropyrrolo-[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl instead of (6aR,8R)-2-chloro-8-(4-formylphenoxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl, and 5-fluoro-2-hydroxyphenylboronic acid instead of (3,5-difluoro-2-hydroxyphenyl)boronic acid.21 H 23 FN5O3[M+H] + LCMS calculated for: m / z=412.2, found: 412.1.

[0356] Step 4: (6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylic acid [ka]

[0357] A solution of tert-butyl (6aR,8R)-8-cyano-2-(3-fluoro-2-hydroxyphenyl)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (60.0 mg, 146 μmol) in NMP (1.00 mL) was treated with 11.6 M aqueous HCl (1.00 mL, 11.6 mmol). The reaction was stirred at 100° C. for 2 hours. The reaction was cooled to room temperature, filtered, diluted with MeOH, and the filtrate was directly purified via preparative HPLC (Waters CSH-C18, 5 μM, 30 × 100 mm, 8.1–28.1% MeCN / water (containing 0.1% TFA) over 5 min) to afford the TFA salt of the title compound (6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo-[1′,2′:4,5]pyrazino[2,3-c]pyridazine-8-carboxylic acid (30.0 mg, 62% yield). 16 H 16 FN4O3[M+H] + LCMS calculated for: m / z=331.1, found: 330.9.

[0358] Step 5: (3R,5S)-4-((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazine-1-carboxylate tert-butyl [ka]

[0359] A mixture of (6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo-[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylic acid (16.0 mg, 48.4 μmol), (3R,5S)-tert-butyl 3,5-dimethylpiperazine-1-carboxylate (15.6 mg, 72.7 μmol), HATU (36.8 mg, 96.9 μmol), and N,N-diisopropylethylamine (33.7 μL, 194 μmol) in DMF (1.00 mL) was stirred at room temperature for 2 hours and treated with 11.6 M aqueous HCl (1.00 mL, 11.6 mmol). The reaction was filtered, diluted with MeOH, and the filtrate was directly purified via preparative HPLC (Waters CSH-C18, 5 μM, 30 × 100 mm, 24.9–44.9% MeCN / water (with 0.1% TFA) over 5 min) to afford the TFA salt of the title compound (3R,5S)-4-((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazine-1-carboxylate (1.60 mg, 6.3% yield). 27 H 36 FN6O4[M+H] + LCMS calculated for: m / z=527.3, found: 527.2.

[0360] Step 6: ((2R,6S)-2,6-dimethylpiperazin-1-yl)((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methanone [ka]

[0361] A 4N HCl solution in 1,4-dioxane (320 μL, 10.3 mmol) was added to a solution of tert-butyl (3R,5S)-4-((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo-[1′,2′:4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazine-1-carboxylate (11.6 mg, 3.04 μmol) in DCM (1.00 mL). The reaction was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give the HCl salt of ((2R,6S)-2,6-dimethylpiperazin-1-yl)((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino-[2,3-c]pyridazin-8-yl)methanone (36.8 mg, 96.9 μmol). 22 H 28 FN6O2[M+H] + LCMS calculated for: m / z=427.2, found: 427.2.

[0362] Step 7: 3-(6-(4-(((3R,5S)-4-((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[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

[0363] The title compound was prepared by replacing 2-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)thio)pyrimidine-5-carbaldehyde with ((2R,6S)-2,6-dimethylpiperazin-1-yl)((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1', Prepared using a procedure similar to that described for Example 26, Step 5, utilizing 1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-4-carbaldehyde (Intermediate 3) in place of 2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methanone; dihydrochloride, and 3-(3-oxo-5-piperazin-1-yl-1H-isoindol-2-yl)piperidine-2,6-dione (Intermediate 2). 41 H 49 FN9O5[M+H] + LCMS calculated for: m / z=766.4, found: 766.2. Example 35: 3-(6-(4-((6-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)(methyl)amino)pyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0364] Step 1: (6aR,8R)-2-chloro-N-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-amine [ka]

[0365] A 40% solution of methylamine in water (1.00 mL, 24.3 mmol) was added to a solution of tert-butyl (6aR,8S)-2-chloro-8-((methylsulfonyl)oxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (25.0 mg, 61.7 μmol, intermediate from Example 34, Step 1) in ethanol (500 μL). The reaction was stirred at 100 °C overnight. The reaction was cooled to room temperature and concentrated under reduced pressure to give (6aR,8R)-2-chloro-N-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-amine (14.0 mg, 95% yield). 10 H 15 ClN5[M+H] + LCMS calculated for: m / z=240.1, found: 240.1.

[0366] Step 2: 6-(((6aR,8R)-2-chloro-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)(methyl)amino)nicotinaldehyde [ka]

[0367] A mixture of (6aR,8R)-2-chloro-N-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]-pyrazino[2,3-c]pyridazin-8-amine (14.0 mg, 58.4 μmol), 2-fluoropyridine-5-carbaldehyde (7.31 mg, 58.4 μmol), and N,N-diisopropylethylamine (20.3 μL, 117 μmol) in DMSO (1.00 mL) was stirred at 110° C. for 2 hours. The reaction was cooled to room temperature, diluted in MeOH, filtered, and purified via preparative HPLC (Waters CSH-C18, 5 μM, 30 × 100 mm, 6.4–26.4% MeCN / water (containing 0.1% TFA) over 5 min) to afford the title compound 6-(((6aR,8R)-2-chloro-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)(methyl)amino)nicotinaldehyde TFA salt (15.0 mg, 75% yield). 16 H 18 ClNO[M+H] + LCMS calculated for: m / z=345.1, found: 345.1.

[0368] Step 3: 3-(6-(4-((6-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)(methyl)amino)pyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0369] The title compound was prepared using procedures similar to those described for Example 1, Step 2 and Step 4, using the appropriate starting materials and intermediates. 39 H 42 FN 10 O4 [M+H] + LCMS calculated for: m / z=733.3, found: 733.3. Example 36: 3-(6-(4-(4-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-methylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0370] Step 1: (2S,4R)-2-(azidomethyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine [ka]

[0371] 2,2,2-Trifluoroacetic acid (5.00 mL, 65.3 mmol) was added to a solution of tert-butyl (2S,4R)-2-(azidomethyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate (1.40 g, 3.93 mmol, prepared as described for Intermediate 1, Step 4) in DCM (6.00 mL). The reaction was stirred at room temperature for 1 hour. The reaction was basified to a pH of approximately 12 using 2 N aqueous NaOH. The layers were separated and the aqueous phase was extracted with DCM (3 × 25.0 mL). The combined organics were washed with saturated brine solution, dried over MgSO, filtered, and concentrated under reduced pressure to provide (2S,4R)-2-(azidomethyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine (900 mg, 89% yield). The material was used in the next step without further purification. C 11 H 25 N4OSi[M+H] + LCMS calculated for: m / z=257.2, found: 257.1.

[0372] Step 2: (6aS,8R)-2-chloro-8-hydroxy-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]-pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl ester [ka]

[0373] The title compound was prepared using a procedure similar to that described for Intermediate 1, steps 6-9. 14 H 20 ClN4O3[M+H] + LCMS calculated for: m / z=327.1 / 329.1, found: 327.8 / 328.9.

[0374] Step 3: (6aS,8S)-2-chloro-8-((4-nitrobenzoyl)oxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl ester [ka]

[0375] Diisopropyl azodicarboxylate (84.0 μL, 427 μmol) was added dropwise to a solution of tert-butyl (6aS,8R)-2-chloro-8-hydroxy-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (70.0 mg, 214 μmol), 4-nitrobenzoic acid (71.6 mg, 428 μmol), and triphenylphosphine (112 mg, 428 μmol) in THF at 0° C. The reaction was heated to 60° C. and stirred for 1 hour. The mixture was cooled to room temperature and quenched with water. The mixture was directly purified via SiOFCC: 0-100% EtOAc / hexanes to give tert-butyl (6aS,8S)-2-chloro-8-((4-nitrobenzoyl)oxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (100 mg, quantitative yield). 21 H 23 ClNO[M+H] + LCMS calculated for: m / z=476.1, found: 476.1.

[0376] Step 4: (6aS,8S)-2-chloro-8-hydroxy-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]-pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl ester [ka]

[0377] Lithium hydroxide (35.0 mg, 1.46 mmol) was added to a solution of tert-butyl (6aS,8S)-2-chloro-8-((4-nitrobenzoyl)oxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (100 mg, 210 μmol) in a mixture of MeOH (1.00 mL), THF (1.00 mL), and water (1.00 mL). The reaction was stirred at room temperature for 1 hour. The mixture was diluted with water and then extracted with ethyl acetate. The organics were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified via SiOFCC: 0-10% MeOH / DCM to give tert-butyl (6aS,8S)-2-chloro-8-hydroxy-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (45.0 mg, 65% yield). 14 H 20 ClN4O3[M+H] + LCMS calculated for: m / z=327.1, found: 327.1.

[0378] Step 5: 3-(6-(4-(4-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-methylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0379] The title compound was prepared using procedures similar to those described for Example 1, Steps 1-4, using the appropriate starting materials and intermediates. 40 H 42 FN8O5[M+H] + LCMS calculated for: m / z=733.3, found: 733.2.

[0380] Example 37 Example 37, shown below in Table 3, was prepared as the TFA salt by the method used to prepare Example 36, utilizing the appropriate starting materials and intermediates. [Table 3] Example 38: (S)-3-(6-(4-((6-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)thio)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0381] Step 1: (6aR,8R)-2-chloro-8-((5-formyl-4-methylpyridin-2-yl)thio)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl ester [ka]

[0382] The title compound was prepared using procedures similar to those described for Example 26, Steps 2-3, using the appropriate intermediates and starting materials. 21 H 25 ClNOS[M+H] + LCMS calculated for: m / z=462.1 / 464.1, found: 462.1 / 464 / 1.

[0383] Step 2: (S)-3-(6-(4-((6-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)thio)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0384] The title compound was prepared using procedures similar to those described for Example 27, Steps 4-7 and Example 26, Step 4, using the appropriate intermediates and starting materials. 39 H 40 F2N9O4S[M+H] + LCMS calculated for: m / z=768.3, found: 768.2. Example 39: 3-(6-(4-((4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0385] Step 1: (6aR,8R)-8-((1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)oxy)-2-chloro-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl ester [ka]

[0386] A mixture of tert-butyl (6aR,8S)-2-chloro-8-((methylsulfonyl)oxy)-6a,7,8,9-tetra-hydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (100 mg, 0.247 mmol, intermediate from Example 34, Step 1), tert-butyl 4-hydroxypyrazole-1-carboxylate (182 mg, 0.988 mmol), and potassium carbonate (172 mg, 1.24 mmol) in NMP (2.00 mL) was stirred overnight at 100° C. The reaction was cooled to room temperature, diluted with water, and the aqueous phase was extracted with DCM. The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure to give a crude mixture of tert-butyl (6aR,8R)-8-((1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)oxy)-2-chloro-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate and tert-butyl 4-(((6aR,8R)-2-chloro-5,6,6a,7,8,9-hexa-hydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-1H-pyrazole-1-carboxylate (122 mg). 22 H 30 ClN6O5[M+H] + LCMS calculated for: m / z=493.2 / 495.2, found: 493.1 / 495.1.

[0387] Step 2: (6aR,8R)-8-((1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)oxy)-2-chloro-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl ester [ka]

[0388] (6aR,8R)-8-((1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)oxy)-2-chloro-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-Butyl 4-(((6aR,8R)-2-chloro-5,6,6a,7,8,9-hexahydropyrrolo[ To a mixture of tert-butyl 1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-1H-pyrazole-1-carboxylate (122 mg, 0.247 mmol) was added 4-(dimethylamino)pyridine (30.2 mg, 0.247 mmol) and di-tert-butyl dicarbonate (270 mg, 1.24 mmol) in NMP (2.00 mL). The reaction was stirred at room temperature for 1 hour. The crude reaction mixture was directly purified via SiOFCC: 0-100% EtOAc / hexanes to afford tert-butyl (6aR,8R)-8-((1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)oxy)-2-chloro-6a,7,8,9-tetrahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate (122 mg, quantitative yield). 22 H 30 ClN6O5[M+H] + LCMS calculated for: m / z=493.2 / 495.2, found: 493.1 / 495.1.

[0389] Step 3: (6aR,8R)-8-((1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)oxy)-2-(3,5-difluoro-2-methoxyphenyl)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl ester [ka]

[0390] The title compound was prepared using a procedure similar to that described for Example 1, Step 2, utilizing (6aR,8R)-8-((1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)oxy)-2-chloro-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl instead of (6aR,8R)-2-chloro-8-(4-formylphenoxy)-6a,7,8,9-tetrahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate tert-butyl, and (3,5-difluoro-2-methoxyphenyl)boronic acid instead of (3,5-difluoro-2-hydroxyphenyl)boronic acid. 29 H 35 F2N6O6[M+H] + LCMS calculated for: m / z = 601.3, found: 601.2.

[0391] Step 4: (6aR,8R)-8-((1H-pyrazol-4-yl)oxy)-2-(3,5-difluoro-2-methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine [ka]

[0392] 2,2,2-Trifluoroacetic acid (0.835 mL, 10.9 mmol) was added to a solution of (6aR,8R)-8-((1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)oxy)-2-(3,5-difluoro-2-methoxyphenyl)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-tert-butyl (65.5 mg, 0.109 mmol) in DCM (2.00 mL). The reaction was stirred at room temperature for 3 hours. The reaction was neutralized with a saturated aqueous solution of NaHCO and extracted with DCM. The combined organics were washed with saturated aqueous brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give (6aR,8R)-8-((1H-pyrazol-4-yl)oxy)-2-(3,5-difluoro-2-methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine (43.7 mg, quantitative yield). The material was used without further purification. C 19 H 19 F2N6O2[M+H] + LCMS calculated for: m / z=401.2, found: 401.1.

[0393] Step 5: 3-(6-(4-((4-(((6aR,8R)-2-(3,5-difluoro-2-methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0394] The title compound was prepared by the procedure of (6aR,8R)-8-((1H-pyrazol-4-yl)oxy)-2-(3,5-difluoro-2-methoxy-phenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate instead of tert-butyl (6aR,8R)-8-((5-(chloromethyl)-4-methylpyridin-2-yl)oxy)-2-(3,5-difluoro-2-methoxy-phenyl)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate. Prepared using a procedure similar to that described for Example 27, Step 7, utilizing hydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine and (1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-4-yl)methyl 4-methylbenzenesulfonate (Intermediate 4) instead of 3-(3-oxo-5-piperazin-1-yl-1H-isoindol-2-yl)piperidine-2,6-dione (Intermediate 2). 38 H 40 LCMS calculated for F2N9O5 [M+H]+: m / z = 740.3, found: 740.4.

[0395] Step 6: 3-(6-(4-((4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0396] The title compound was prepared by the reaction of 3-(6-(4-((4-((6aR,8R)-2-(3,5-difluoro-2-methoxyphenyl)-8-((5-formylpyrimidin-2-yl)thio)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine-5(6H)-carboxylate with tert-butyl 3-(6-(4-((4-((6aR,8R)-2-(3,5-difluoro-2- Prepared using a procedure similar to that described for Example 26, Step 4, utilizing methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. 37 H 38 LCMS calculated for F2N9O5 [M+H]+: m / z = 726.3, found: 726.3. Example 40: 3-(6-(4-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylpyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0397] Step 1. 1-(tert-butyl) 2-methyl (2S,4R)-4-(benzyloxy)pyrrolidine-1,2-dicarboxylate: [ka]

[0398] Iodomethane (3.0 mL, 48.2 mmol) was added to a stirred solution of (2S,4R)-4-(benzyloxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (6.2 g, 19.3 mmol) and potassium carbonate (3.32 g, 24 mmol) in DMF (46.4 mL). The reaction was stirred at room temperature for 2 hours. The product mixture was diluted with EtOAc (200 mL). The diluted product mixture was washed with water (200 mL) and saturated aqueous sodium chloride solution (2 x 200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was used without further purification. 1-(tert-butyl) 2-methyl(2S,4R)-4-(benzyloxy)pyrrolidine-1,2-dicarboxylate was obtained as a yellow oil (6.46 g, 99%). C 13 H 18 NO3[M+H-C5H9O2] + LCMS calculated for: m / z=236.1, found: 236.1.

[0399] Step 2. 1-(tert-butyl) 2-methyl (4R)-4-(benzyloxy)-2-(difluoromethyl)pyrrolidine-1,2-dicarboxylate [ka]

[0400] Lithium bis(trimethylsilyl)amide (1 M in THF, 30 mL, 30 mmol) was added to a stirred solution of 1-(tert-butyl) 2-methyl(2S,4R)-4-(benzyloxy)pyrrolidine-1,2-dicarboxylate (6.7 g, 20 mmol) in THF (100 mL) at −78° C. The reaction mixture was allowed to warm slowly to room temperature for 45 minutes. The reaction mixture was then cooled to −78° C. Difluoromethyl trifluoromethanesulfonate (5.06 mL, 39.9 mmol) was added dropwise to the reaction mixture at −78° C. The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The product mixture was diluted with saturated aqueous ammonium chloride solution (200 mL) and stirred for 10 minutes. The diluted product mixture was transferred to a separatory funnel and extracted with EtOAc (200 mL). The organic layer was washed with saturated aqueous sodium chloride solution (2×200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography using a gradient of 0-50% EtOAc / hexanes to afford 1-(tert-butyl) 2-methyl (4R)-4-(benzyloxy)-2-(difluoromethyl)pyrrolidine-1,2-dicarboxylate as an inseparable mixture of diastereomers (5.6 g, 73%). 14 H 18 F2NO3[M+H-C5H9O2] + LCMS calculated for: m / z=286.1, found: 286.0.

[0401] Step 3. (4R)-4-(benzyloxy)-1-(tert-butoxycarbonyl)-2-(difluoromethyl)pyrrolidine-2-carboxylic acid [ka]

[0402] An aqueous solution of sodium hydroxide (2.5 M, 58.4 mL, 146 mmol) was added to a stirred solution of 1-(tert-butyl) 2-methyl(4R)-4-(benzyloxy)-2-(difluoromethyl)pyrrolidine-1,2-dicarboxylate (5.6 g, 14.5 mmol) in THF (27 mL) and MeOH (27 mL) at room temperature. The reaction mixture was heated to 65 °C and stirred for 2 h. The product mixture was cooled to room temperature and acidified with an aqueous solution of hydrochloric acid (1 M, 160 mL, 160 mmol). The acidified product mixture was transferred to a separatory funnel and extracted with EtOAc (2 × 200 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was used without further purification. (4R)-4-(benzyloxy)-1-(tert-butoxycarbonyl)-2-(difluoromethyl)pyrrolidine-2-carboxylic acid was obtained as an orange oil (5.4 g, 100%). 13 H 16 F2NO3[M+H-C5H9O2] + LCMS calculated for: m / z=272.1, found: 271.9.

[0403] Step 4. (4R)-4-(benzyloxy)-2-((4-bromo-6-chloropyridazin-3-yl)carbamoyl)-2-(difluoromethyl)pyrrolidine-1-carboxylate tert-butyl ester [ka]

[0404] 1-[Bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (6.55 g, 17.2 mmol) was added to a stirred solution of (4R)-4-(benzyloxy)-1-(tert-butoxycarbonyl)-2-(difluoromethyl)pyrrolidine-2-carboxylic acid (5.77 g, 15.5 mmol) and N,N-diisopropylethylamine (9.72 mL, 55.8 mmol) in acetonitrile (75 mL). The reaction mixture was stirred for 40 minutes at room temperature. The product mixture was concentrated under reduced pressure. The resulting residue was dissolved in THF (62.4 mL). 4-Bromo-6-chloro-pyridazin-3-amine (4.2 g, 20.2 mmol) was added to the solution, and the resulting solution was stirred. Sodium hydride (2.2 g, 55.2 mmol, 60% dispersion in mineral oil) was added portionwise to the stirred reaction mixture at room temperature. After 1 h, the product mixture was cooled to 0 °C and quenched with saturated aqueous ammonium chloride (100 mL). The quenched product mixture was transferred to a separatory funnel and diluted with water (100 mL). The diluted product mixture was extracted with EtOAc (2 × 200 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 0–50% EtOAc / hexanes to give tert-butyl (4R)-4-(benzyloxy)-2-((4-bromo-6-chloropyridazin-3-yl)carbamoyl)-2-(difluoromethyl)pyrrolidine-1-carboxylate (5.4 g, 62%). 22 H 25 BrClF2N4O4[M+H] + LCMS calculated for: m / z=561.1, found: 561.9.

[0405] Step 5. (6aS,8R)-8-(benzyloxy)-2-chloro-6a-(difluoromethyl)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-6(5H)-one and (6aR,8R)-8-(benzyloxy)-2-chloro-6a-(difluoromethyl)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-6(5H)-one [ka]

[0406] Trifluoroacetic acid (7.36 mL, 96.1 mmol) was added to a stirred solution of tert-butyl (4R)-4-(benzyloxy)-2-((4-bromo-6-chloropyridazin-3-yl)carbamoyl)-2-(difluoromethyl)-pyrrolidine-1-carboxylate (5.4 g, 9.61 mmol) at room temperature. The reaction mixture was stirred for 5 hours. The product mixture was concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (15 mL). N,N-Diisopropylethylamine (8.37 mL, 48.1 mmol) was added to the stirred reaction mixture. The reaction mixture was heated to 80° C. and stirred for 16 hours. The product mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography using a gradient of 0-100% EtOAc / hexanes to give (6aS,8R)-8-(benzyloxy)-2-chloro-6a-(difluoromethyl)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-6(5H)-one (562 mg, 15%) and (6aR,8R)-8-(benzyloxy)-2-chloro-6a-(difluoromethyl)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-6(5H)-one (1.87 g, 51%). 17 H 16 ClF2N4O2[M+H] + LCMS calculated for: m / z=381.1, found: 381.0.

[0407] Step 6. (6aS,8R)-8-(benzyloxy)-6a-(difluoromethyl)-2-(3-fluoro-2-methoxyphenyl)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-6(5H)-one [ka]

[0408] A 20 mL scintillation vial was charged with (6aS,8R)-8-(benzyloxy)-2-chloro-6a-(difluoromethyl)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-6(5H)-one (400 mg, 1.05 mmol), cesium carbonate (1.37 g, 4.2 mmol), 3-fluoro-2-methoxyphenylboronic acid (357 mg, 2.1 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (129 mg, 0.16 mmol). The solid mixture was dissolved in 1,4-dioxane (8 mL) and water (0.8 mL). The reaction mixture was sparged with N gas for 5 min, sealed, and heated to 100 °C. The reaction mixture was stirred at 100°C for 1 hour. The product mixture was diluted with EtOAc (50 mL). The diluted product mixture was washed with saturated aqueous sodium bicarbonate (50 mL). The aqueous layer was extracted with EtOAc (2 x 50 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 / hexanes to give (6aS,8R)-8-(benzyloxy)-6a-(difluoromethyl)-2-(3-fluoro-2-methoxyphenyl)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-6(5H)-one (318 mg, 64%). 24 H 22 F3N4O3[M+H] + LCMS calculated for: m / z=471.2, found: 471.0.

[0409] Step 7. (6aS,8R)-8-(benzyloxy)-6a-(difluoromethyl)-2-(3-fluoro-2-methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine [ka]

[0410] Lithium aluminum hydride (1.0 M in THF, 2.03 mL, 2.03 mmol) was added to a stirred solution of (6aS,8R)-8-(benzyloxy)-6a-(difluoromethyl)-2-(3-fluoro-2-methoxyphenyl)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-6(5H)-one (318 mg, 0.68 mmol) in THF (6 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 1.5 h. The reaction mixture was cooled to 0 °C and quenched by the slow addition of methanol (7.7 mL). The reaction mixture was warmed to room temperature. Acetic acid (770 μL, 13.5 mmol) and sodium cyanoborohydride (428 mg, 6.81 mmol) were added sequentially to the reaction mixture at room temperature. The reaction mixture was heated to 80 °C and stirred for 14 h. The product mixture was cooled to room temperature and transferred to a separatory funnel containing saturated potassium carbonate solution (100 mL). The diluted product mixture was extracted with EtOAc (4 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography using a gradient of 0–15% MeOH / DCM to afford (6aS,8R)-8-(benzyloxy)-6a-(difluoromethyl)-2-(3-fluoro-2-methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine (290 mg, 94%) as a white foamy solid. 24 H 24 F3N4O2[M+H] + LCMS calculated for: m / z=457.2, found: 457.1.

[0411] Step 8. (6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol and (6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol [ka]

[0412] Boron trichloride (1.0 M in DCM, 3.29 mL, 3.29 mmol) was added dropwise to a stirred solution of (6aS,8R)-8-(benzyloxy)-6a-(difluoromethyl)-2-(3-fluoro-2-methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine (500 mg, 1.1 mmol) in DCM (11.5 mL) at -78 °C. The reaction mixture was warmed to 0 °C and stirred for 30 min. The product mixture was quenched with water (5 mL) and transferred to a separatory funnel containing saturated aqueous sodium carbonate (100 mL). The quenched product mixture was extracted with a 3:1 chloroform:isopropanol solution (4 × 100 mL). The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography using a gradient of 0-20% MeOH / DCM to give (6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol (221 mg, 55%) and (6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol (83 mg, 21%). 17 H 18F3N4O2[M+H] + LCMS calculated value for m / z = 367.1, found value: 367.0. 16 H 16 F3N4O2[M+H] + LCMS calculated for: m / z=353.1, found: 353.0.

[0413] Step 9. Methyl 5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylpyrazine-2-carboxylate [ka]

[0414] Sodium hydride (55 mg, 1.38 mmol, 60% dispersion in mineral oil) was added to a stirred solution of methyl 5-chloro-6-methylpyrazine-2-carboxylate (171.2 mg, 0.92 mmol) and (6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol (84 mg, 0.23 mmol) in THF (2.5 mL) at 0 °C. The reaction mixture was warmed to 35 °C and stirred for 1.5 h. The product mixture was cooled to 0 °C and quenched with saturated aqueous ammonium chloride (30 mL). The quenched product mixture was transferred to a separatory funnel and extracted with a 3:1 chloroform:isopropanol solution (3 × 30 mL). The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography using a gradient of 0-15% MeOH / DCM to give methyl 5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylpyrazine-2-carboxylate (104 mg, 88%). 24 H 24 F3N6O4[M+H] + LCMS calculated for: m / z=517.2, found: 517.0.

[0415] Step 10. (5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylpyrazin-2-yl)methanol [ka]

[0416] Diisobutylaluminum hydride (1.0 M in toluene, 0.81 mL, 0.81 mL) was added to a stirred solution of methyl 5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylpyrazine-2-carboxylate (104 mg, 0.20 mmol) in THF (4 mL) at −78° C. The reaction mixture was warmed to 0° C. and stirred for 1 h. The reaction mixture was quenched with saturated aqueous potassium sodium tartrate (30 mL) and stirred at room temperature for 30 min. The quenched reaction mixture was transferred to a separatory funnel and extracted with 3:1 chloroform:isopropanol solution (3 × 30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in methanol (3 mL) and cooled to 0°C. Sodium borohydride (22.8 mg, 0.6 mmol) was added to the reaction mixture at 0°C and stirred for 30 minutes. The product mixture was transferred to a separatory funnel containing saturated aqueous ammonium chloride solution (30 mL) and extracted with a 3:1 chloroform:isopropanol solution (3 x 30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography using a gradient of 0-20% MeOH / DCM to give 5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylpyrazin-2-yl)methanol (88 mg, 89%). 23 H 24 F3N6O3[M+H] + LCMS calculated for: m / z=489.2, found: 489.0.

[0417] Step 11. 2-((6aS,8R)-8-((5-(chloromethyl)-3-methylpyrazin-2-yl)oxy)-6a-(difluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)-6-fluorophenol [ka]

[0418] Boron trichloride (1.0 M in DCM, 2.7 mL, 2.7 mmol) was added to a stirred solution of (5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylpyrazin-2-yl)methanol (88 mg, 0.18 mmol) in DCM (1 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 16 h. The product mixture was cooled to 0°C and quenched by the slow addition of water (2 mL). The quenched product mixture was transferred to a separatory funnel containing saturated aqueous potassium carbonate (30 mL) and extracted with a 3:1 chloroform:isopropanol solution (4 x 30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in THF (1 mL). The reaction mixture was cooled to 0 °C. Thionyl chloride (39.3 μL, 0.54 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was warmed to room temperature and stirred for 30 minutes. The product mixture was diluted with water (10 mL), transferred to a separatory funnel containing saturated aqueous potassium carbonate (30 mL), and extracted with a 3:1 chloroform:isopropanol solution (4 × 30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give 2-((6aS,8R)-8-((5-(chloromethyl)-3-methylpyrazin-2-yl)oxy)-6a-(difluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)-6-fluorophenol (88 mg, 99%). The residue was used directly in the next step without further purification.22 H 21 ClF3N6O2[M+H] + LCMS calculated for: m / z=493.1, found: 493.0.

[0419] Step 12: 3-(6-(4-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylpyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Example 40) [ka]

[0420] N,N-Diisopropylethylamine (156 μL, 0.89 mmol) was added to a stirred solution of 2-((6aS,8R)-8-((5-(chloromethyl)-3-methylpyrazin-2-yl)oxy)-6a-(difluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-2-yl)-6-fluorophenol (88 mg, 0.18 mmol) and (S)-3-(1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione; hydrochloride (97.7 mg, 0.27 mmol) in acetonitrile (5 mL) at room temperature. The reaction mixture was heated to 120° C. and stirred for 1.5 hours. The product mixture was cooled to room temperature, diluted with DMSO, and filtered through Celite. The diluted product mixture was directly purified by preparative HPLC (Waters CSH-Fluoro-Phenyl, 5 μM, 30 × 100 mm, 10.1–30.1% MeCN / water (with 0.1% TFA) over 5 min) to give 3-(6-(4-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylpyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (50.4 mg, 25%) as its TFA salt.

[0421] 1H NMR(400MHz,MeOD)δ 8.19(s,1H),7.51(d,J=8.2Hz,1H),7.40-7.29(m,4H),7.08(s,1H),7.02(td,J=8.1,4.8Hz,1H),6. 27(t,J=55.6Hz,1H),5.87(t,J=7.6Hz,1H),5.13(dd,J=13.3,5.2Hz,1H),4.53-4.34(m,4H),4.08(d ,J=12.6Hz,1H),4.00(dd,J=13.2,3.0Hz,1H),3.26(d,J=3.9Hz,1H),2.98-2.84(m,1H),2.81-2.76 (m,1H),2.74(d,J=14.8Hz,1H),2.56(s,3H),2.54-2.40(m,2H),2.17(dtd,J=12.9,5.3,2.5Hz,1H). C 39 H 40 F3N 10 O5 [M+H] + LCMS calculated for: m / z=785.3, found: 785.1. Example 41: 3-(6-(4-((2-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxy-phenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4,6-dimethylpyrimidin-5-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0422] Step 1. 5-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloro-4,6-dimethylpyrimidine [ka]

[0423] Diisobutylaluminum hydride (1.0 M in toluene, 5.59 mL, 5.59 mmol) was added dropwise to a stirred solution of ethyl 2-chloro-4,6-dimethylpyrimidine-5-carboxylate (480.0 mg, 2.24 mmol) in THF (12.8 mL) at −78° C. The reaction mixture was allowed to warm slowly to room temperature over 3 hours. The reaction mixture was stirred at room temperature for 1 hour. The product mixture was quenched with saturated aqueous potassium sodium tartrate solution (15 mL) and stirred for 30 minutes. The quenched product mixture was transferred to a separatory funnel containing saturated aqueous potassium sodium tartrate solution (70 mL) and extracted with EtOAc (3×80 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in DCM (13 mL). Imidazole (305 mg, 4.47 mmol) and tert-butyldimethylchlorosilane (506 mg, 3.35 mmol) were added sequentially to the stirred reaction mixture. The reaction mixture was stirred for 30 minutes. The product mixture was filtered through Celite and concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography using a gradient of 0-50% EtOAc / hexanes to give 5-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloro-4,6-dimethylpyrimidine (213 mg, 33%). 13 H 24 ClN2OSi[M+H] + LCMS calculated for: m / z = 287.1, found: 287.0.

[0424] Step 2. (6aS,8R)-8-((5-(((tert-butyldimethylsilyl)oxy)methyl)-4,6-dimethylpyrimidin-2-yl)oxy)-6a-(difluoromethyl)-2-(3-fluoro-2-methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine [ka]

[0425] Sodium hydride (11 mg, 0.27 mmol, 60% dispersion in mineral oil) was added to a stirred solution of 5-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloro-4,6-dimethyl-pyrimidine (39 mg, 0.14 mmol) and (6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol (20 mg, 0.05 mmol) in THF (2 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 1 h. The product mixture was cooled to 0 °C and quenched by the slow addition of methanol (1 mL). The quenched product mixture was transferred to a separatory funnel containing saturated aqueous ammonium chloride (35 mL) and extracted with ethyl acetate (3 × 35 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography using a 0–10% MeOH / DCM gradient to afford (6aS,8R)-8-((5-(((tert-butyldimethylsilyl)oxy)methyl)-4,6-dimethylpyrimidin-2-yl)oxy)-6a-(difluoromethyl)-2-(3-fluoro-2-methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine (23 mg, 68%). 30 H 40 F3N6O3Si[M+H] + LCMS calculated for: m / z=617.3, found: 617.1.

[0426] Step 3. 2-((6aS,8R)-8-((5-(chloromethyl)-4,6-dimethylpyrimidin-2-yl)oxy)-6a-(difluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)-6-fluorophenol [ka]

[0427] Boron trichloride (1.0 M in DCM, 1.19 mL, 1.19 mmol) was added to a stirred solution of (6aS,8R)-8-((5-(((tert-butyldimethylsilyl)oxy)-4,6-dimethylpyrimidin-2-yl)oxy)-6a-(difluoromethyl)-2-(3-fluoro-2-methoxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine (23 mg, 0.037 mmol) in DCM (1 mL) at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 24 hours. An additional portion of boron trichloride (1.0 M in DCM, 1.19 mL, 1.19 mmol) was added to the reaction mixture and stirred for an additional 48 hours. The product mixture was allowed to warm to room temperature and stirred for 24 hours. The mixture was cooled to RT. The product mixture was quenched with water (2 mL). The quenched product mixture was transferred to a separatory funnel containing saturated aqueous potassium carbonate (30 mL). The diluted product mixture was extracted with a 3:1 chloroform:isopropanol solution (4 x 30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give 2-((6aS,8R)-8-((5-(chloromethyl)-4,6-dimethylpyrimidin-2-yl)oxy)-6a-(difluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)-6-fluorophenol. The residue was used directly in the next step without further purification. C 23 H 23 ClF3N6O2[M+H] + LCMS calculated for: m / z=507.2, found: 507.1.

[0428] Step 4: 3-(6-(4-((2-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4,6-dimethylpyrimidin-5-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Example 41) [ka]

[0429] N,N-Diisopropylethylamine (18.9 μL, 0.11 mmol) was added to a stirred solution of 2-((6aS,8R)-8-((5-(chloromethyl)-4,6-dimethylpyrimidin-2-yl)oxy)-6a-(difluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-2-yl)-6-fluorophenol (11 mg, 0.022 mmol) and (S)-3-(1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione; hydrochloride (11.9 mg, 0.33 mmol) in acetonitrile (1 mL) at room temperature. The reaction mixture was heated to 120° C. and stirred for 1.5 hours. The product mixture was cooled to room temperature, diluted with DMSO, and filtered through Celite. The diluted product mixture was directly purified by preparative HPLC (Waters CSH-C18, 5 μM, 30 × 100 mm, 10.1–30.1% MeCN / water (with 0.1% TFA) over 5 min) to give 3-(6-(4-((2-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4,6-dimethylpyrimidin-5-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (8.7 mg, 35%) as its TFA salt.

[0430] 1H NMR(400MHz,MeOD)δ 7.50(d,J=8.3Hz,1H),7.40-7.30(m,4H),7.09(s,1H),7.02(td,J=8.1,4.8Hz,1H),6.32(t, J=55.5Hz,1H),5.87(t,J=7.1Hz,1H),5.13(dd,J=13.3,5.2Hz,1H),4.53-4.33(m,5H),4.13 (d,J=12.7Hz,1H),4.02(dd,J=13.2,2.8Hz,1H),3.25(d,J=3.5Hz,1H),2.96-2.84(m,1H),2 .82-2.73(m,1H),2.69(d,J=12.0Hz,1H),2.66(s,6H),2.56-2.41(m,2H),2.23-2.12(m,1H). C 40 H 42 F3N 10 O5 [M+H] + LCMS calculated for: m / z=799.3, found: 799.2. Example 42: 3-(6-(4-((2-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyrimidin-5-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0431] Step 1. 5-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloropyrimidine [ka]

[0432] Diisobutylaluminum hydride (1.0 M in toluene, 3.19 mL, 3.19 mmol) was added to a stirred solution of methyl 2-chloropyrimidine-5-carboxylate (220 mg, 1.27 mmol) in THF (6 mL) at −78° C. The reaction mixture was allowed to warm slowly to room temperature. The product mixture was quenched with saturated aqueous potassium sodium tartrate (20 mL) and stirred at room temperature for 30 minutes. The quenched product mixture was diluted with EtOAc (50 mL) and transferred to a separatory funnel containing saturated aqueous potassium sodium tartrate (30 mL). The diluted product mixture was extracted with EtOAc (2×50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in DCM (6 mL). Imidazole (278 mg, 4.09 mmol) and tert-butyldimethylsilyl chloride (308 mg, 2.04 mmol) were added sequentially to the reaction mixture. The reaction mixture was stirred for 30 minutes. The product mixture was filtered through Celite and concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography using a gradient of 0-50% EtOAc / hexanes to give 5-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloropyrimidine (210 mg, 64%). 11 H 20 ClN2OSi[M+H] + LCMS calculated for: m / z=259.1, found: 259.0.

[0433] Step 2. 3-(6-(4-((2-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyrimidin-5-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Example 42) [ka]

[0434] This example was synthesized by a procedure similar to that described in Example 41, using 5-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloropyrimidine instead of 5-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloro-4,6-dimethylpyrimidine.

[0435] 1 H NMR(400MHz,MeOD)δ 8.80(s,2H),7.50(d,J=8.3Hz,1H),7.39-7.28(m,4H),7.09(s,1H),7.02(td,J=8.0,4.8Hz,1H) ,6.30(t,J=55.5Hz,1H),5.89(t,J=7.2Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.51-4.31(m,5H) ,4.12(d,J=12.6Hz,1H),4.05(dd,J=13.1,2.9Hz,1H),3.48(br,7H)3.30-3.24(m,1H),2.96-2. 84(m,1H),2.80(dd,J=4.8,2.5Hz,1H),2.78-2.68(m,2H),2.57-2.42(m,2H),2.23-2.11(m,1H). C 38 H 38 F3N 10 O5 [M+H] + LCMS calculated for: m / z=771.3, found: 771.2. Example 43: (S)-3-(6-(4-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0436] Step 1. 5-(1,3-Dioxolan-2-yl)-2-fluoropyridine [ka]

[0437] p-Toluenesulfonic acid (3.4 g, 20 mmol) was added to a stirred solution of 6-fluoronicotinaldehyde (25 g, 0.20 mol) and ethylene glycol (25 g, 0.40 mol) in toluene (250 mL). The reaction mixture was heated to 110 °C and stirred for 1 h. The product mixture was cooled to room temperature and quenched with saturated aqueous sodium bicarbonate. The quenched product mixture was extracted twice with EtOAc. The combined organic layers were washed with saturated sodium chloride solution, then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using a 0-10% EtOAc / hexane gradient to give 5-(1,3-dioxolan-2-yl)-2-fluoropyridine (22.6, 67%). C8H9FNO2 [M+H] + LCMS calculated for: m / z=170.1, found: 170.3.

[0438] Step 2. (6aR,8R)-8-(benzyloxy)-2-chloro-6a-(difluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine [ka]

[0439] Sodium borohydride (1.49 g, 39.4 mmol) was added to a stirred solution of (6aR,8R)-8-(benzyloxy)-2-chloro-6a-(difluoromethyl)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-6(5H)-one (5.0 g, 13.1 mmol) in THF (50 mL), followed by the dropwise addition of BF₃·t₂O (7.45 g, 52.5 mmol) at 15–25 °C. The mixture was stirred at 25 °C for 16 h. The mixture was cooled to 0 °C, quenched with MeOH (5 mL), and stirred for 30 min. The mixture was concentrated in vacuo to give the crude product (4.82 g), which was used in the next step without further purification. Acetic acid (7.56 g, 125.9 mol) and sodium cyanoborohydride (3.96 g, 62.9 mmol) were added sequentially to a stirred solution of the crude product (4.82 g) in EtOH (50 mL) and heated to reflux for 2 h. The mixture was cooled to 25 °C and quenched by the addition of water (50 mL). The product solution was concentrated under reduced pressure to remove EtOH. The mixture was basified to pH 7-8 with saturated aqueous sodium bicarbonate and extracted with EtOAc (30 mL × 2). The combined organic phases were washed with saturated aqueous sodium chloride (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue that was purified by silica gel flash column chromatography using a gradient of 50-100% MTBE / hexanes to give (6aR,8R)-8-(benzyloxy)-2-chloro-6a-(difluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine (4.78 g, 99%) as a white solid. 17 H 18 ClF2N4O[M+H] + LCMS calculated for: m / z=367.1, found: 367.0.

[0440] Step 3. (6aR,8R)-2-chloro-6a-(difluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol [ka]

[0441] (6aR,8R)-8-(benzyloxy)-2-chloro-6a-(difluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine (35 g) was dissolved in DCM (700 mL) in a three-necked 2000 mL flask. The solution was cooled to -5 °C, and boron trichloride (1 M, 280 mL, 280 mmol) was added to the mixture while maintaining the temperature below -5 °C. The mixture was stirred below -5 °C for 1 hour. MeOH (175 mL) was added to the mixture while allowing the temperature to rise below 10 °C. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using a gradient of 0-10% DCM / MeOH to give (6aR,8R)-2-chloro-6a-(difluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol (25.1 g, 95%). 10 H 12 ClF2N4O[M+H] + LCMS calculated for: m / z=277.1, found: 277.3.

[0442] Step 4. (6aR,8R)-8-((5-(1,3-dioxolan-2-yl)pyridin-2-yl)oxy)-2-chloro-6a-(difluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine [ka]

[0443] Sodium hydride (105 mg, 2.6 mmol, 60% dispersion in mineral oil) was added to a stirred solution of (6aR,8R)-2-chloro-6a-(difluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol (243 mg, 0.87 mmol) in dimethylacetamide (2.4 mL) at room temperature. The reaction mixture was heated to 80 °C, and 5-(1,3-dioxolan-2-yl)-2-fluoropyridine (156 mg, 0.92 mmol) was added to the reaction mixture. The reaction mixture was stirred at 80 °C until consumption of the starting material was observed. The product mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride (3 mL). The quenched product mixture was transferred to a separatory funnel and extracted with DCM (2 × 3 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (3 mL) and washed with saturated aqueous sodium chloride (3 x 2 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using a gradient of 0-66% EtOAc / DCM to give the title compound (250 mg, 67%). 18 H 19 ClF2N5O3[M+H] + LCMS calculated for: m / z=426.1, found: 426.2.

[0444] Step 5. 2-((6aR,8R)-8-((5-(1,3-dioxolan-2-yl)pyridin-2-yl)oxy)-6a-(difluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)-6-fluorophenol [ka]

[0445] (6aR,8R)-8-((5-(1,3-dioxolan-2-yl)pyridin-2-yl)oxy)-2-chloro-6a-(difluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine (220 mg, 0.56 mmol), (3-fluoro-2-hydroxyphenyl)boronic acid (121 mg, 0.78 mmol), potassium phosphate tribasic (415 mg, 1.96 mmol), and Xphos Pd G2 (44 mg, 0.056 mmol) were added to a degassed solution of 1,4-dioxane (2.2 mL) and water (0.22 mL). The reaction mixture was heated to 100 °C for 1.5 h. The product mixture was diluted with water (2.5 mL) and DCM (3 mL). The aqueous layer was extracted with DCM (3 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using a gradient of 0-50% EtOAc / DCM to give the title compound (124 mg, 48%). 24 H 23 F3N5O4[M+H] + LCMS calculated for: m / z=502.2, found: 502.3.

[0446] Step 6. 6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)nicotinaldehyde [ka]

[0447] Trifluoroacetic acid (0.83 mL, 1.08 mol) was added dropwise to 2-((6aR,8R)-8-((5-(1,3-dioxolan-2-yl)pyridin-2-yl)oxy)-6a-(difluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)-6-fluorophenol (166 mg, 0.33 mmol). The reaction mixture was heated to 55°C and stirred overnight. The product mixture was quenched with saturated aqueous sodium bicarbonate and extracted twice with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (151 mg, 100%), which was used without further purification. C 22 H 19 F3N5O3[M+H] + LCMS calculated for: m / z=458.1, found: 458.3.

[0448] Step 7. (S)-3-(6-(4-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Example 43) [ka]

[0449] N,N-Diisopropylethylamine (213 mg, 1.65 mmol) was added to a stirred solution of 6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)nicotinaldehyde (151 mg, 0.33 mmol) and (S)-3-(1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione; hydrochloride (240 mg, 0.66 mmol) in a solution of DMSO (1.5 mL). The reaction mixture was heated to 45°C and stirred for 2 hours. The reaction mixture was cooled to room temperature. Sodium triacetoxyborohydride (210 mg, 0.99 mmol) was added to the reaction mixture at room temperature. The reaction mixture was heated to 35° C. and stirred for 16 hours. The product mixture was quenched with water and extracted twice with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give (S)-3-(6-(4-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (114 mg, 45%).

[0450] 1H NMR(400MHz,CD3OD)δ 8.46(d,J=2.3Hz,1H),8.08(dd,J=8.7,2.4Hz,1H),7.49(d,J=8.8Hz,1H),7.38-7.29(m,4H),7.10(s,1H),7.06-6.9 6(m,2H),6.20(t,J=55.7Hz,1H),5.90(s,1H),5.11(dd,J=13.3,5.1Hz,1H),4.47(s,2H),4.44-4.34(m,2H),4.29(dd ,J=12.9,6.1Hz,1H),4.11-3.97(m,2H),3.89(s,2H),3.61(s,2H),3.45-3.33(m,3H),3.25(s,2H),3.08(dd,J=14.5 ,6.9Hz,1H),2.95-2.83(m,1H),2.77(ddd,J=17.5,4.5,2.3Hz,1H),2.48(qd,J=13.2,4.7Hz,1H),2.31-2.11(m,2H). C 39 H 39 F3N9O5[M+H] + LCMS calculated for: m / z=770.3, found: 770.8. Example 44: (S)-3-(6-(4-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-ethylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0451] Step 1. 5-Bromo-3-ethylpyridin-2-amine [ka]

[0452] N-Bromosuccinimide (1460 mg, 8.19 mmol) was added to a stirred solution of 3-ethylpyridin-2-amine (1.0 g, 8.19 mmol) in MeCN (30 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then warmed to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography using a gradient of 0-10% MeOH / DCM to give 5-bromo-3-ethylpyridin-2-amine (1.52 g, 92%). CH 10 BrN2[M+H] + LCMS calculated for: m / z=201.0, found: 201.0.

[0453] Step 2. 5-Bromo-3-ethylpyridin-2-ol [ka]

[0454] Sodium nitrite (2.57 g, 37.3 mmol) dissolved in water (15 mL) was added over 15 minutes at 0° C. to a stirred solution of 5-bromo-3-ethylpyridin-2-amine (600 mg, 2.98 mmol) and sulfuric acid (18.4 M, 19.2 mL, 360.2 mmol) in water (65 mL). The reaction mixture was stirred at 0° C. for 2 hours. The product mixture was diluted with water (50 mL) and extracted with a 3:1 chloroform:isopropanol solution (4×100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give 5-bromo-3-ethylpyridin-2-ol (603 mg, 100%), which was used without further purification. C7H9BrNO[M+H] + LCMS calculated for: m / z=202.0, found: 202.0.

[0455] Step 3. 3-Ethyl-5-vinylpyridin-2-ol [ka]

[0456] A 40 mL scintillation vial was charged with vinylboronic acid pinacol ester (1.82 mL, 10.7 mmol), 5-bromo-3-ethylpyridin-2-ol (542 mg, 2.68 mmol), XPhos Pd G2 (105 mg, 0.134 mmol), and potassium carbonate (1.85 g, 13.4 mmol). The mixture was dissolved in 1,4-dioxane (10 mL) and water (3 mL). The reaction mixture was sparged with N2 gas for 5 minutes, sealed, and heated to 100 °C. The reaction mixture was stirred at 100 °C for 1 hour. The product mixture was diluted with MeOH (10 mL), filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography using a gradient of 0-20% MeOH / DCM to give 3-ethyl-5-vinylpyridin-2-ol (385 mg, 96%). CH 12 NO[M+H] + LCMS calculated value for: m / z=150.1, found value: 150.0.

[0457] Step 4. 1-(tert-butyl) 2-methyl (2R,4S)-4-(benzyloxy)pyrrolidine-1,2-dicarboxylate [ka]

[0458] Sodium hydride (2.45 g, 61.2 mmol, 60% dispersion in mineral oil) was added to a stirred solution of 1-(tert-butyl) 2-methyl(2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (10.0 g, 40.8 mmol) in THF (100 mL) at 0° C. The reaction mixture was stirred for 30 minutes. Benzyl bromide (7.27 mL, 61.2 mmol) was added to the stirred reaction mixture at 0° C. The reaction mixture was warmed to room temperature and stirred for 3 hours. The product mixture was poured into saturated aqueous ammonium chloride solution (200 mL) and extracted with DCM (3×150 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 0-50% EtOAc / hexanes to afford 1-(tert-butyl) 2-methyl(2R,4S)-4-(benzyloxy)pyrrolidine-1,2-dicarboxylate (10.7 g, 78%). 13 H 18 NO3[M+H-C5H9O2] + LCMS calculated for: m / z=236.1, found: 236.0.

[0459] Step 5. (6aR,8S)-8-(benzyloxy)-2-chloro-6a-(difluoromethyl)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-6(5H)-one [ka]

[0460] This intermediate was synthesized by a procedure similar to that described in Example 40, using 1-(tert-butyl)2-methyl(2R,4S)-4-(benzyloxy)pyrrolidine-1,2-dicarboxylate instead of 1-(tert-butyl)2-methyl(2S,4R)-4-(benzyloxy)pyrrolidine-1,2-dicarboxylate in Step 2 of Example 40. 17 H 16 ClF2N4O2[M+H] +LCMS calculated for: m / z=381.1, found: 380.9.

[0461] Step 6. (6aR,8S)-8-(benzyloxy)-2-chloro-6a-(difluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine [ka]

[0462] Borane dimethyl sulfide complex (2.0 M in THF, 3.28 mL, 6.57 mmol) was added to a stirred solution of (6aR,8S)-8-(benzyloxy)-2-chloro-6a-(difluoromethyl)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-6(5H)-one (1.00 g, 2.63 mmol) in THF (13.4 mL) at room temperature. The reaction mixture was heated to 55°C and stirred for 2 hours. The reaction mixture was cooled to room temperature, and a second portion of borane dimethyl sulfide complex (2.0 M, 1.00 mL, 2.00 mmol) was added. The reaction mixture was heated to 55°C and stirred for an additional 2 hours. The reaction mixture was cooled to 0°C and quenched by the slow addition of MeOH (10 mL). The quenched reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in EtOH (21.4 mL). Acetic acid (2.98 mL, 52.03 mmol) and sodium cyanoborohydride (397 mg, 6.31 mmol) were added sequentially to the reaction mixture. The reaction mixture was heated to 70° C. and stirred for 30 hours. The product mixture was cooled to 0° C. and quenched with saturated aqueous sodium bicarbonate (150 mL). The diluted product mixture was extracted with DCM (3×200 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 0-10% MeOH / DCM to give (6aR,8S)-8-(benzyloxy)-2-chloro-6a-(difluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine (573 mg, 60%). 17 H 18 ClF2N4O[M+H] + LCMS calculated for: m / z=367.1, found: 367.0.

[0463] Step 7. (6aR,8S)-2-chloro-6a-(difluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol [ka]

[0464] Boron trichloride (1.0 M in DCM, 4.69 mL, 4.69 mmol) was added to a stirred solution of (6aR,8S)-8-(benzyloxy)-2-chloro-6a-(difluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine (573 mg, 1.56 mmol) in DCM (15.6 mL) at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. The product mixture was quenched by the slow addition of saturated aqueous sodium bicarbonate (60 mL). The diluted product mixture was extracted with a 3:1 chloroform:isopropanol solution (4 x 100 mL). The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure to give (6aR,8S)-2-chloro-6a-(difluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol as a white solid (420 mg, 97%). 10 H 12 ClF2N4O[M+H] + LCMS calculated for: m / z = 277.1, found: 276.9.

[0465] Step 8. (6aR,8R)-2-chloro-6a-(difluoromethyl)-8-((3-ethyl-5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine [ka]

[0466] Diisopropyl azodicarboxylate (64.0 μL, 0.33 mmol) was added to a stirred solution of polymer-bound triphenylphosphine (approximately 1.6 mmol / g, 203 mg, 0.33 mmol), 3-ethyl-5-vinylpyridin-2-ol (97.1 mg, 0.65 mmol), and (6aR,8S)-2-chloro-6a-(difluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol (60 mg, 0.217 mmol) in THF (3 mL). The reaction mixture was heated to 60 °C and stirred for 1 h. The product mixture was filtered, and the solid was washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel flash column chromatography using a gradient of 0-10% MeOH / DCM to give (6aR,8R)-2-chloro-6a-(difluoromethyl)-8-((3-ethyl-5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine (43 mg, 49%). 19 H 21 ClF2N5O[M+H] + LCMS calculated for: m / z=408.1, found: 408.1.

[0467] Step 9. 2-((6aR,8R)-6a-(difluoromethyl)-8-((3-ethyl-5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)-6-fluorophenol [ka]

[0468] A 20 mL scintillation vial was charged with 3-fluoro-2-hydroxyphenylboronic acid (91.8 mg, 0.588 mmol), (6aR,8R)-2-chloro-6a-(difluoromethyl)-8-((3-ethyl-5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine (80 mg, 0.196 mmol), XPhos Pd G2 (15.4 mg, 0.020 mmol), and potassium carbonate (136 mg, 0.98 mmol). The mixture was dissolved in 1,4-dioxane (1.5 mL) and water (400 μL). The reaction mixture was sparged with N2 gas for 5 minutes, sealed, and heated to 80 °C. The reaction mixture was stirred at 80 °C for 1 hour. The product mixture was transferred to a separatory funnel containing saturated sodium bicarbonate solution (40 mL) and extracted with a 3:1 chloroform:isopropanol solution (3 x 30 mL). The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography using a gradient of 0-10% MeOH / DCM to afford the title compound (90 mg, 95%). 25 H 25 F3N5O2[M+H] + LCMS calculated for: m / z=484.2, found: 484.0.

[0469] Step 10. 6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-ethylnicotinaldehyde [ka]

[0470] Osmium tetroxide (4% in water, 118 μL, 0.0186 mmol) was added to a stirred solution of 2-((6aR,8R)-6a-(difluoromethyl)-8-((3-ethyl-5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-2-yl)-6-fluorophenol (90 mg, 0.186 mmol) and 4-methylmorpholine N-oxide (110 mg, 0.931 mmol) in THF (780 μL), water (250 μL), and tert-butanol (200 μL). The reaction mixture was stirred at room temperature for 3 hours. The product mixture was quenched with saturated aqueous sodium sulfite (10 mL). The quenched product mixture was transferred to a separatory funnel and diluted with water (10 mL) and saturated aqueous sodium chloride (10 mL). The diluted product mixture was extracted with a 3:1 chloroform:isopropanol solution (3 x 30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in MeCN (1 mL) and water (1 mL). Sodium periodate (159 mg, 0.74 mmol) was added to the reaction mixture and stirred at room temperature for 30 minutes. The product mixture was transferred to a separatory funnel containing saturated aqueous sodium bicarbonate (30 mL). The diluted product mixture was extracted with a 3:1 chloroform:isopropanol solution (3 x 30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (70 mg, 78%). The resulting residue was used directly in the next step. C 24 H 23 F3N5O3[M+H] + LCMS calculated for: m / z=486.2, found: 486.0.

[0471] Step 11. (S)-3-(6-(4-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-ethylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Example 44) [ka]

[0472] N,N-Diisopropylethylamine (37.7 μL, 0.216 mmol) was added to a stirred solution of 6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-ethylnicotinaldehyde (70 mg, 0.072 mmol) and (S)-3-(1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione; hydrochloride (52.6 mg, 0.144 mmol) in DMSO (566 μL). The reaction mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (45.8 mg, 0.216 mmol) was added to the reaction mixture. The reaction mixture was heated to 35° C. and stirred for 18 h. The product mixture was diluted with DMSO and purified directly by preparative HPLC (Waters CSH-phenyl-hexyl, 5 μM, 30 × 100 mm, 7.2–25.2% MeCN / water (containing 0.1% TFA) over 12 min) to afford the title compound (19.7 mg, 27%) as its TFA salt.

[0473] 1H NMR(600MHz,DMSO)δ 10.90(s,1H),9.90(s,1H),8.10(s,1H),7.66(s,1H),7.43(d,J=8.4Hz,2H),7.32-7.23(m,2H),7.20(d,J=2.4Hz,1H),7.13(s,1H),6.89- 6.83(m,1H),6.27(t,J=55.4Hz,1H),5.76(p,J=5.8Hz,1H),5.03(dd,J=13.3,5.1Hz,1H),4.34-4.26(m,3H),4.17(d,J=16.9Hz,1H),4.09 (dd,J=12.8,6.2Hz,1H),3.94-3.76(m,4H),3.26-3.19(m,2H),3.11(s,2H),2.98(s,2H),2.84(ddt,J=13.8,9.4,5.5Hz,2H),2.58-2.50( m,1H),2.46(d,J=8.7Hz,1H),2.38-2.27(m,1H),2.07(dd,J=14.2,5.1Hz,1H),1.92(dtd,J=12.9,5.5,2.4Hz,1H),1.05(t,J=7.5Hz,3H). C 41 H 43 F3N9O5[M+H] + LCMS calculated for: m / z=798.3, found: 798.0. Example 45: (S)-3-(6-(4-((5-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-fluoro-4-methylpyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0474] Step 1. 5-Bromo-3-fluoro-4-methylpyridin-2-amine [ka]

[0475] N-Bromosuccinimide (776 mg, 4.36 mmol) was added to a stirred solution of 3-fluoro-4-methylpyridin-2-amine (500 mg, 3.96 mmol) in MeCN (20 mL). The reaction mixture was heated to 50 °C and stirred for 30 min. The product mixture was concentrated and directly purified by silica gel flash column chromatography using a gradient of 0-50% EtOAc / hexanes to give 5-bromo-3-fluoro-4-methylpyridin-2-amine (538 mg, 66%). CHBrFN [M+H] + LCMS calculated for: m / z=205.0, found: 204.9.

[0476] Step 2. 5-Bromo-3-fluoro-2-iodo-4-methylpyridine [ka]

[0477] Isoamyl nitrite (528 μL, 3.94 mmol) was added to a stirred solution of 5-bromo-3-fluoro-4-methylpyridin-2-amine (538 mg, 2.62 mmol) in diiodomethane (2.0 mL, 24.8 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 10 minutes. Copper(I) iodide (250 mg, 1.31 mmol) and iodine (799 mg, 3.15 mmol) were added sequentially to the reaction mixture. The reaction mixture was stirred for 48 hours. The product mixture was quenched with saturated aqueous sodium thiosulfate solution (30 mL). The quenched product mixture was extracted with DCM (3×30 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography using a gradient of 0-25% EtOAc / hexanes to give 5-bromo-3-fluoro-2-iodo-4-methylpyridine (377 mg, 45%). CHBrFIN [M+H] + LCMS calculated for: m / z=315.9, found: 315.7.

[0478] Step 3. 5-Bromo-3-fluoro-4-methyl-2-vinylpyridine [ka]

[0479] A 20 mL scintillation vial was charged with 5-bromo-3-fluoro-2-iodo-4-methylpyridine (377 mg, 1.19 mmol), vinylboronic acid pinacol ester (306 μL, 1.79 mmol), potassium carbonate (330 mg, 2.39 mmol), and [1,1'-bis(diphenylphosphino)ferrocen...

Claims

1. Compounds of formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein: R １ But, Halo, C １－６ Alkyl, or C １－６ is haloalkyl, Each R ２ is independently H, D, or F; Each R ３ But independently, H, D, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ heterocycloalkyl, or C ３－６ is cycloalkyl, n is 1, 2, or 3; m is 1, 2, 3, or 4; R ４ But H, D, C １－６ Alkyl, C １－６ Alkoxyalkyl, C ３－６ cycloalkyl, or C １－６ is haloalkyl, R ５ is H, D, or F; L １ is a bond, O, S, S(O), SO ２ , N.R. ３ , C(R ３ ) ２ or CO, L ２ is a bond, O, S, S(O), SO ２ , N.R. ３ , C(R ３ ) ２ or CO, Ring A １ is a 6-membered aryl group or a 5- to 6-membered heteroaryl group, Ring A ２ is a 3- to 7-membered cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, X １ But CH ２ , CO, CH=CH(X ２ =CO), or N = CH (X ２ =CO), X ２ But CH ２ , CO, CH=CH(X １ =CO), or N = CH (X １ =CO), The alkyl group, haloalkyl group, cycloalkyl group, alkoxyalkyl group, aryl group, heteroaryl group, or heterocycloalkyl group may be one or more R ｆ optionally substituted by a group, Each R ｆ are independently selected from D, oxo, halogen, C １ -C ８ Alkoxy, C １ -C ８ Alkyl, C １－６ Haloalkyl, C １－６ Haloalkoxy, —OH, —CN, —NO2, —C2-C6 alkenyl, —C2-C6 alkynyl, C ６－１０ Aryl, C ５－１２ Heteroaryl, C ３－８ Cycloalkyl, C ３－８ Cycloalkenyl, C ３－８ Heterocycloalkyl, C ３－８ heterocycloalkenyl, —OR ａ , -SR ａ , -NR ｃ R ｄ , -NR ａ R ｃ , -C(O)R ｂ , -OC(O)R ｂ , -C(O)OR ｂ , —C(O)NR ｃ R ｄ , -S(O)R ｂ , -S(O)NR ｃ R ｄ , -S(O)(=NR ｂ ) R ｂ , -SF5, -P(O)R ｂ R ｂ , -P(O)R ｃ R ｄ , -P(O)(OR ｂ ) (OR ｂ ), -B(OR ｃ ) (OR ｄ ), -S(O)R ｂ , —C(O)NR ｂ OR ｂ , -S(O) ２ OR ｂ , -OS(O) ２ OR ｂ , or -OPO(OR ｂ ) (OR ｂ ) wherein C １ -C ８ Alkyl is D, halogen, —OH, —CN, —OR ａ , -SR ａ , -NR ａ R ｄ , or NR ｃ R ｄ and optionally substituted with 1 to 6 groups selected from Each R ａ are independently H, D, -C(O)R ｂ , -C(O)OR ｃ , —C(O)NR ｃ R ｄ , -C(=NR ｂ ) NR ｂ R ｃ 、 -C(=NOR ｂ ) NR ｂ R ｃ 、 -C(=NCN)NR ｂ R ｃ 、 -P(OR ｃ ) ２ , -P(O)R ｃ R ｂ , -P(O)R ｃ R ｄ , -P(O)OR ｃ OR ｂ , -S(O)R ｂ , -S(O)NR ｃ R ｄ , -S(O) ２ R ｂ , -S(O) ２ NR ｃ R ｄ , SiR ｂ ３ , -C １ -C １０ Alkyl, —C ２ -C １０ Alkenyl, -C ２ -C １０ Alkynyl, C ６－１０ Aryl, C ３－８ Cycloalkyl, C ３－８ Cycloalkenyl, C ５－１２ Heteroaryl, C ３－８ heterocycloalkyl, or C ３－８ heterocycloalkenyl, Each R ｂ However, independently, H, D, -C １ -C ６ Alkyl, —C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, C ６－１０ Aryl, C ３－８ Cycloalkyl, C ３－８ Cycloalkenyl, C ５－１２ Heteroaryl, C ３－８ heterocycloalkyl, or C ３－８ heterocycloalkenyl, Each R ｃ or R ｄ However, independently, H, D, -C １ -C １０ Alkyl, —C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, —OC １ -C ６ Alkyl, —O-cycloalkyl, C ６－１０ Aryl, C ５－１２ Heteroaryl, C ３－８ Cycloalkyl, C ３－８ Cycloalkenyl, C ３－８ heterocycloalkyl, or C ３－８ heterocycloalkenyl, or Or R ｃ and R ｄ is taken together with the atom to which they are both attached to form a monocyclic or polycyclic heterocycloalkyl, or a monocyclic or polycyclic heterocycloalkenyl group, or a pharmaceutically acceptable salt thereof.

2. R １ The compound of claim 1 , wherein is halo.

3. R １ The compound according to claim 1 or 2, wherein is F.

4. 10. 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. Each R ２ A compound according to any one of the preceding claims, wherein is F.

8. Each R ２ The compound of any one of claims 1 to 6, wherein is H.

9. 10. 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. Each R ３ A compound according to any one of the preceding claims, wherein is H.

14. R ４ A compound according to any one of the preceding claims, wherein is H.

15. R ４ The compound according to any one of claims 1 to 13, wherein is D.

16. R ４ But C １－６ The compound of any one of claims 1 to 13, which is alkyl.

17. R ４ The compound according to any one of claims 1 to 13, wherein is methyl.

18. R ５ A compound according to any one of the preceding claims, wherein is H.

19. L １ A compound according to any one of the preceding claims, wherein is O.

20. L １ But NR ３ The compound according to any one of claims 1 to 18, wherein

21. L １ The compound according to any one of claims 1 to 18, wherein is S.

22. L ２ 10. A compound according to any one of the preceding claims, wherein is CO.

23. L ２ But C(R ３ ) ２ The compound according to any one of claims 1 to 21,

24. L ２ The compound according to any one of claims 1 to 21, wherein is a methylene group.

25. Ring A １ 10. A compound according to any one of the preceding claims, wherein is a six-membered aryl group.

26. Ring A １ 26. The compound of claim 25, wherein is a phenyl group.

27. Ring A １ The compound of any one of claims 1 to 24, wherein is a 5- to 6-membered heteroaryl group.

28. Ring A １ 28. The compound of claim 27, wherein is a pyridine group.

29. Ring A ２ A compound according to any one of the preceding claims, wherein is a 4- to 7-membered heterocycloalkyl group.

30. Ring A ２ 30. The compound of claim 29, wherein is a piperidine group or a piperazine group.

31. X １ But CH ２ 10. A compound according to any one of the preceding claims, wherein

32. X １ The compound according to any one of claims 1 to 30, wherein is CO.

33. X ２ But CH ２ 10. A compound according to any one of the preceding claims, wherein

34. X ２ The compound according to any one of claims 1 to 32, wherein is CO.

35. A compound of formula IIa or IIb: 【Chemistry 2】 or a pharmaceutically acceptable salt thereof.

36. Compounds of Formula IIIa or IIIb: 【Chemistry 3】 or a pharmaceutically acceptable salt thereof, wherein: Each Z is independently N or CR ６ and Each R ６ are independently H, D, halo, -CN, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ haloalkoxy, or C ３－６ 10. A compound according to any one of the preceding claims which is cycloalkyl.

37. 37. The compound of claim 36, wherein at least one Z is N.

38. 38. The compound of claim 36 or 37, wherein at least two Z's are N.

39. At least one Z is CR ６ The compound according to any one of claims 36 to 38, wherein

40. At least two Z's are CR ６ The compound according to any one of claims 36 to 39, wherein

41. At least one R ６ The compound of any one of claims 36 to 40, wherein is H.

42. At least one R ６ But C １－６ The compound of any one of claims 36 to 40, which is alkyl.

43. At least one R ６ 43. The compound of claim 42, wherein is methyl.

44. Compounds of Formula IVa or IVb: 【Chemistry 4】 or a pharmaceutically acceptable salt thereof, wherein Z １ But N or CR ６ The compound according to any one of claims 36 to 43, wherein

45. Z １ 45. The compound of claim 44, wherein is N.

46. Z １ But, CR ６ 45. The compound of claim 44, wherein:

47. A compound of formula Va or formula Vb: 【Chemistry 5】 or a pharmaceutically acceptable salt thereof.

48. A compound of formula VIa or formula VIb: 【Chemistry 6】 or a pharmaceutically acceptable salt thereof.

49. A compound of formula VIIa or VIIb: 【Chemistry 7】 or a pharmaceutically acceptable salt thereof.

50. 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)benzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-methylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(5-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-fluorobenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)benzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(3-chloro-4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)benzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-methylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3-chloro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)benzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2,5-dimethylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3-chloro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-methylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-methylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-methoxybenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-fluorobenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-isopropylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-(trifluoromethyl)benzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-isopropylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2,6-dimethylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2,3-dimethylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3-chloro-5-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-methylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(2-hydroxy-3-methylphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-methylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3-chloro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-methoxybenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3-chloro-5-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)benzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(2-hydroxy-3-methylphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)benzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-(trifluoromethoxy)benzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-(4-(((6aR,8R)-2-(3-chloro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)benzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((2-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)thio)pyrimidin-5-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((6-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((6-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((6-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((6-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((6-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((6-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((6-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[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-((6-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)(methyl)amino)pyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-(4-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-methylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(1-(4-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-methylbenzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((6-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)thio)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((4-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or a pharmaceutically acceptable salt thereof.

51. 3-(6-(4-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylpyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((2-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4,6-dimethylpyrimidin-5-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((2-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyrimidin-5-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-ethylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-fluoro-4-methylpyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3,4-dimethylpyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((6-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-ethylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3,6-dimethylpyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((2-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-isopropylpyrimidin-5-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-methylpyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((6-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-methoxypyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((6-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-fluoropyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((6-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((6-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-methylpyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((6-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 5-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)methyl)-2-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylnicotinonitrile, 3-(6-(4-((6-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)thio)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((6-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-fluoro-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((6-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2,4-dimethylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((6-(((6aR,8R)-2-(3,5-difluoro-2-hydroxyphenyl)-6a-ethyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylpyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((5-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylpyrazin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylpyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((6-ethyl-5-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((6-ethyl-5-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyrazin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-fluoro-6-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((5-fluoro-6-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-fluoro-6-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-exahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-fluoropyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(5-(4-((5-(((6aS,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-(trifluoromethyl)pyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(5-(4-((5-(((6aS,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-methylpyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((2-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4,6-dimethylpyrimidin-5-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 5-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)methyl)-2-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)isonicotinonitrile, (S)-3-(6-(1-((2-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyrimidin-5-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((2-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4,6-dimethylpyrimidin-5-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyrazin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3,6-dimethylpyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-methylpyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((5-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-methylpyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((6-(((6aS,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-methyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-fluoropyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(4-((5-chloro-6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4,5-dimethylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(4-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-2,5-dimethylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(1-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-fluoropyridin-3-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((6-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-5-fluoro-4-methylpyridin-3-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-6-methylpyrazin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((6-(((6aR,8R)-2-(3-fluoro-2-hydroxyphenyl)-6a-(fluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((5-(((6aS,8R)-6a-(difluoromethyl)-2-(2-hydroxy-3-methylphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((5-(((6aR,8R)-6a-ethyl-2-(2-hydroxy-3-methylphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3,4-dimethylpyridin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((2-(((6aS,8R)-6a-ethyl-2-(2-hydroxy-3-methylphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4,6-dimethylpyrimidin-5-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((5-(((6aS,8R)-6a-ethyl-2-(2-hydroxy-3-methylphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-methylpyridin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((3-chloro-5-(((6aS,8R)-2-(3-chloro-2-hydroxyphenyl)-6a-ethyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((6-(((6aR,8R)-2-(3-chloro-2-hydroxyphenyl)-6a-ethyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((5-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-fluoropyridin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((2-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4,6-dimethylpyrimidin-5-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((5-(((6aS,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyrazin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((5-(((6aS,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-3-methylpyridin-2-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(6-(1-((2-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyrimidin-5-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(1-((6-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 3-(6-(1-((6-(((6aR,8R)-6a-ethyl-2-(3-fluoro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-4-methylpyridin-3-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or a pharmaceutically acceptable salt thereof.

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

53. 10. 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.

54. 54. A method of treating cancer in a subject in need thereof, comprising administering to said subject a compound according to any one of claims 1 to 52 or a pharmaceutical composition according to claim 53.

55. 55. The method of claim 54, wherein the cancer is a SMARCA4 deficient cancer.

56. The cancers include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and renal cell carcinoma, cancer of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate and stomach; leukemia; benign and malignant lymphoma, in particular Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma.

56. The method of claim 54 or 55, wherein the cancer is a sarcoma, including ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, and Schwannoma; colorectal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratocarcinoma.

57. 57. The method of any one of claims 54 to 56, 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, B-cell precursor ALL, B-cell precursor lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, and Philadelphia chromosome positive CML.

58. 57. The method of claim 56, wherein the lung cancer is a SMARCA4-deficient non-small cell lung cancer.

59. A method for degrading a SMARCA protein, the method comprising contacting the SMARCA protein with a compound according to any one of claims 1 to 52 or a pharmaceutical composition according to claim 53.

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