BRM targeting compounds and related methods of use

Abstract

The present disclosure relates to compounds of formula (I). Also described are pharmaceutical compositions comprising the compounds of Formula (I) and methods for their use and preparation. # imgabs0 # (I).

Description

Technical Field

[0001] This specification provides bifunctional compounds comprising a target protein binding moiety and an E3 ubiquitin ligase binding moiety, and related methods of use. The bifunctional compounds are useful as modulators of targeted ubiquitination, particularly for Switch / Sucrose Non-Fermentable (SWI / SNF)-Related, Matrix-Associated, Actin-Dependent Regulator of Chromatin, Subfamily A, Member 2 (SMARCA2) (i.e., BRAHMA or BRM), which is degraded and / or otherwise inhibited by the bifunctional compounds according to the present disclosure. Background Art

[0002] The human Switch / Sucrose Non-Fermentable (SWI / SNF) complex is an ATP-dependent chromatin remodeling factor. These large complexes play important roles in essential cellular processes such as transcription, DNA repair, and replication by regulating DNA accessibility.

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

[0004] SMARCA2 (BRM) and SMARCA4 (BRG1) are subunits containing catalytic ATPase domains, and they are essential for the function of SWI / SNF in the disruption of histone-DNA contacts, thereby providing entry points for transcription factors and cognate DNA elements and facilitating gene activation and repression.

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

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

[0007] It has also been reported that SMARCA2 plays a role in multiple myeloma expressing the t(4;14) chromosomal translocation [Chooi et al., Cancer Res Abstract 2018]. SMARCA2 interacts with NSD2 and regulates gene expression of, for example, PRL3 and CCND1. Downregulation of SMARCA2 gene expression with shRNA shortens the S phase of the cell cycle and inhibits cell proliferation of 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 relates to compounds of formula (I):

[0010] (I)

[0011] or a pharmaceutically acceptable salt thereof; wherein

[0012] R1 is halo, C 1-6 alkyl or haloalkyl;

[0013] Each R2 is independently H, D or F;

[0014] Each R3 is independently H, D, C 1-6 alkyl, haloalkyl, C 3-6 heteroalkyl or C 3-6 cycloalkyl;

[0015] n is 1, 2 or 3;

[0016] m is 1, 2, 3 or 4;

[0017] R4 is H, D, C 1-6 alkyl, C 1-6 alkoxyalkyl, C 3-6 cycloalkyl or C 1-6 haloalkyl;

[0018] R5 is H, D or F;

[0019] L1 is a bond, O, S, S(O), SO2, NR3, C(R3)2 or CO;

[0020] L2 is a bond, O, S, S(O), SO2, NR3, C(R3)2 or CO;

[0021] Ring A1 is a 6-membered aryl or a 5-6-membered heteroaryl;

[0022] Ring A2 is a 3-7-membered cycloalkyl or a 4-7-membered heterocycloalkyl;

[0023] X1 is CH2, CO, CH=CH (when X2 = CO) or N=CH (when X2 = CO);

[0024] X2 is CH2, CO, CH=CH (when X1 = CO) or N=CH (when X1 = CO);

[0025] wherein the alkyl, the haloalkyl, the cycloalkyl, the alkoxyalkyl, the aryl, the heteroaryl or the heterocycloalkyl is optionally substituted by one or more R f groups;

[0026] each Rf independently is D, oxo, halogen, C1-C8 alkoxy, C1-C8 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)2NR c R d 、-S(O)(=NR b )R b 、-SF5、-P(O)Rb R b 、-P(O)R c R d 、-P(O)(OR b )(OR b )、-B(OR c )(OR d )、-S(O)2R 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 optionally substituted by 1-6 groups selected from the following groups: D, halogen, -OH, -CN, -OR a 、-SR a 、-NR a R d or NR c R d ;

[0027] 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)2R b 、-S(O)2NR c R d 、SiR b 3. -C1-C 10 Alkyl, -C2-C 10 Alkenyl, -C2-C 10 Alkynyl, C6-10 Aryl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 5-12 Heteroaryl, C 3-8 Heterocycloalkyl or C 3-8 Heterocycloalkenyl;

[0028] Each R b independently is 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; and

[0029] Each R c or R d independently is H, D, -C1-C 10 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OC1-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;

[0030] or R c and R d together with the atoms to which both are attached form a monocyclic or polycyclic heterocycloalkyl or a monocyclic or polycyclic heterocycloalkenyl.

[0031] Also contemplated, described, and covered herein are the stereoisomers of the compounds of formula I and their pharmaceutically acceptable salts and stereoisomers. Methods of using the compounds of formula I and pharmaceutical compositions comprising the compounds of formula I are described. Detailed Description

[0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. The terms used in this specification are for the purpose of describing particular embodiments only and are not intended to limit the disclosure.

[0033] When providing a range of values, it is to be understood that each intermediate value, to one tenth of the unit of the lower limit, is covered within the present disclosure, unless the context clearly dictates otherwise (e.g., in the case of a group containing multiple carbon atoms, in which case each number of carbon atoms falling within the range is provided), between the upper and lower limits of the range, and any other stated value or intermediate value within that stated range. The upper and lower limits of these smaller ranges, which may independently be included in a smaller range, are also covered within the present disclosure, subject to any specifically excluded limitations within the stated range. When the range includes one or both of the limitations, a range excluding either of the two included limitations is also included within the present disclosure.

[0034] The following terms are used to describe the present disclosure. In cases where a term is not specifically defined herein, the term is given the meaning recognized in the art to which the term pertains as applied by one of ordinary skill in the art in the context of describing the present disclosure.

[0035] As used herein and in the appended claims, the articles “a” and “an” are used herein to refer to one or more than one (e.g., at least one) grammatical object of the article, unless the context clearly dictates otherwise. By way of example, “an element” means one element or more than one element.

[0036] The terms “co-administration” and “co-administering” or “combination therapy” may refer to both simultaneous administration (administering two or more therapeutic agents simultaneously) and time-varying administration (administering one or more therapeutic agents at a different time than another one or more therapeutic agents), provided that the therapeutic agents are present in the patient to some extent, preferably in an effective amount. In certain preferred aspects, one or more of the compounds of the invention described herein are co-administered in combination with at least one additional bioactive agent (bioactive agents particularly including anti-cancer agents). In particularly preferred aspects, co-administration of the compounds results in synergistic activity and / or therapy, including anti-cancer activity.

[0037] In context, unless otherwise stated, as used herein, the term “compound” refers to any specific compound disclosed herein and includes its tautomers, regioisomers, geometric isomers, and, where applicable, stereoisomers, including its optical isomers (enantiomers) and other stereoisomers (diastereomers), as well as pharmaceutically acceptable salts and derivatives thereof, including prodrugs and / or its deuterated forms (where applicable). Deuterated small molecules contemplated are those in which one or more hydrogen atoms contained in the drug molecule have been replaced by deuterium.

[0038] 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) and specific enantiomers or enantiomer-enriched mixtures of the disclosed compounds. In context, 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. It should be noted that in describing the compounds of the present invention, many substituents and variables associated therewith are particularly described. A person of ordinary skill in the art should understand that the molecules described herein are stable compounds as generally described below.

[0039] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein to target the substrate protein for degradation. For example, an E3 ubiquitin ligase protein, which alone or in combination with an E2 ubiquitin-conjugating enzyme causes ubiquitin to attach to a lysine on the target protein and subsequently targets a specific protein substrate for degradation by the proteasome. Thus, the E3 ubiquitin ligase, alone or complexed with an E2 ubiquitin-conjugating enzyme, is responsible for transferring ubiquitin to the target protein. Generally, ubiquitin ligases are involved in polyubiquitination such that a second ubiquitin attaches to the first ubiquitin; a third ubiquitin attaches to the second ubiquitin, and so on. Polyubiquitination marks the protein for degradation by the proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, where only a single ubiquitin is added to the substrate molecule by the ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation, but can, for example, alter their cellular location or function by binding to other proteins that have a domain capable of binding ubiquitin. Even more complex, different lysines of ubiquitin can be targeted by the E3 to form chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to form polyubiquitin that is recognized by the proteasome.

[0040] 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 prevalent E3 ligases and is recruited by bifunctional proteolysis-targeting chimera (PROTAC) to induce ubiquitination and subsequent proteasomal degradation of target proteins (Maniaci C. et al., Bioorg Med Chem. 2019, 27(12): 2466-2479).

[0041] Unless otherwise specified, as used herein, the term "alkyl" by itself or as part of another substituent refers to a straight-chain or branched-chain hydrocarbon group having up to twelve carbon atoms. In some embodiments, the number of carbon atoms is specified (i.e., C 1-C8 means from one to eight carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. The alkyl group can be optionally substituted as provided herein. In some embodiments, the alkyl group is C 1- C6 alkyl; in some embodiments, it is C 1- C4 alkyl.

[0042] When a range of carbon atoms is used herein, such as C1-C6, all ranges and individual carbon atom numbers are encompassed. For example, "C1-C3" includes C 1- C3, C 1- C2, C 2- C3, C1, C2, and C3.

[0043] The term "optionally substituted" as used in combination with substituents defined herein means that the substituent can but does not require that one or more hydrogens be replaced by one or more suitable functional groups or other substituents provided herein. For example, the substituent can be optionally substituted with one or more of the following: halo, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo(C 1-6 )alkyl, C 1-6 alkoxy, halo(C 1-6 alkoxy), C 1-6 alkylthio, C 1-6 alkylamino, NH2, NH(C 1-6 alkyl), N(C 1-6 alkyl)2, NH(C 1-6 alkoxy), N(C 1-6 alkoxy)2, -C(O)NHC 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -C(O)NH2, -C(O)C 1-6 alkyl, -C(O)2C 1-6 alkyl, -NHCO(C 1-6 alkyl), -N(C 1-6 alkyl)CO(C 1-6 alkyl), -S(O)C 1-6 alkyl, —S(O)2C 1-6 alkyl, oxo, 6-12 membered aryl, benzyl, pyridyl, pyrazolyl, thiazolyl, isothiazolyl, or other 5 to 12 membered heteroaryl. In some embodiments, each of the above optional substituents is itself optionally substituted with one or two groups.

[0044] The term "optionally substituted -CH2-" means "-CH2-" or "substituted -CH2-". Substituted -CH2- can also be referred to as -CH(substituent)- or -C(substituent)(substituent)-, where each substituent is independently selected from the optional substituents described herein.

[0045] As used herein, the term "cycloalkyl" refers to a 3- to 12-membered cyclic alkyl group and includes bridged and spiro cyclic groups (e.g., adamantane). The cycloalkyl group can be fully saturated or partially unsaturated. The term "cycloalkyl" also includes multiple fused ring systems (e.g., a ring system containing 2, 3, or 4 rings), where a single cycloalkyl ring (as defined above) can be fused to one or more groups selected from: heterocyclic, carbocyclic, aryl, or heteroaryl to form multiple fused ring systems. Such multiple fused ring systems can optionally be substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic moieties of the multiple fused rings. When valence requirements permit, the rings of the multiple fused ring systems can be interconnected by fusion, spiro, and bridging bonds. It should be understood that the individual rings of the multiple fused ring systems can be connected to each other in any order. It should also be understood that the point of attachment of the polyfused ring system (as defined above for cycloalkyl) can be at any position on the cycloalkyl ring. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclohexyl, cycloheptyl, cyclooctyl, indenyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[4.1.0]heptyl, spiro[3.3]heptyl, and spiro[3.4]octyl. In some embodiments, the cycloalkyl is a 3- to 7-membered cycloalkyl.

[0046] When used alone or as part of a substituent, the term "cycloalkenyl" refers to a monocyclic or polycyclic partially saturated ring structure having from 3 to 10 carbon atoms ("C 3- C 10 "), preferably from 3 to 6 carbon atoms ("C 3- 6"). The cycloalkenyl groups of the present disclosure include monocyclic groups as well as polycyclic groups such as bicyclic and tricyclic groups. In those embodiments having at least one polycyclic cycloalkenyl group, the cyclic groups can share a common atom (i.e., spiro). 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 having between three and six carbon atoms. The cycloalkenyl group can be attached at any carbon atom of the partially saturated ring such that the resulting structure is stable. The cycloalkenyl group includes groups in which the partially saturated ring is fused to an aryl group. Examples of cycloalkenyl include, for example, cyclopropenyl (C3), cyclobutenyl (C4), cyclopropenylmethyl (C4), cyclopentenyl (C5), cyclohexenyl (C6), 1-methylcyclopropenyl (C4), 2-methylcyclopentenyl (C4), adamantyl (C 10), spiro[3.3]heptenyl, bicyclo[3.3.0]octenyl, indanyl, etc. In some embodiments, the cycloalkenyl of the present disclosure is optionally substituted. Unless otherwise specified, in those embodiments where the cycloalkenyl is substituted, the cycloalkenyl may be substituted with one, two, or three substituents independently selected from the following: -OH, -CN, amino, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -OC(O)NH(C1-C6 alkyl), -OC(O)N(C1-C6 alkyl)2, -S(O)2NH(C1-C6 alkyl), and -S(O)2N(C1-C6 alkyl)2. In other embodiments, the cycloalkenyl is optionally substituted with 1-6 groups selected from the following: D, halogen, -OH, -CN, -OR a , -SR a , -NR a R d or NR c R d ; or the cycloalkenyl is optionally substituted with one or more R f groups.

[0047] As used herein, the term "alkenyl" refers to a C 2- C 12 alkyl containing at least one carbon-carbon double bond. In some embodiments, the alkenyl is optionally substituted. In some embodiments, the alkenyl is a C 2- C6 alkenyl.

[0048] As used herein, the term "alkynyl" refers to a C 2- C 12 alkyl containing at least one carbon-carbon triple bond. In some embodiments, the alkenyl is optionally substituted. In some embodiments, the alkynyl is a C 2- C6 alkynyl.

[0049] The terms "alkoxy", "alkylamino", and "alkylthio" are used in their conventional meanings and refer to those alkyl groups attached to the remainder of the molecule through an oxygen atom ("oxy"), an amino group ("amino"), or a sulfur group. The term "alkylamino" includes monoalkylamino / dialkylamino, and the alkyl moieties may be the same or different.

[0050] As used herein, the term "alkoxyalkyl" refers to a straight-chain monovalent hydrocarbon group of one to six carbon atoms or a branched-chain monovalent hydrocarbon group of three to six carbon atoms substituted with an alkoxy group, as defined above, for example, 2-methoxyethyl, 1-methoxypropyl, 2-methoxypropyl, or 3-methoxypropyl, 2-ethoxyethyl, etc.

[0051] The term "halo" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.

[0052] As used herein, the term "haloalkyl" means any alkyl group in which one or more hydrogen atoms are replaced by a halogen atom.

[0053] The term "heteroalkyl" means an alkyl group in which one or more carbon atoms have been replaced by a heteroatom selected from S, O, P and N. Exemplary heteroalkyls include alkyl ethers, secondary alkylamines and tertiary alkylamines, alkyl amides, alkyl sulfides, etc. The group may be a terminal group or a bridging group. As used herein, when referring to a straight chain in the context of a bridging group, it means the direct chain of atoms connecting the two terminal positions of the bridging group.

[0054] As used herein, the term "aryl" means a single fully carbon aromatic ring or multiple fused fully carbon ring systems, wherein at least one ring is aromatic. For example, in certain embodiments, aryl has 6 to 12 carbon atoms. Aryl includes phenyl. Aryl also includes multiple fused ring systems having about 9 to 12 carbon atoms (e.g., a ring system containing 2, 3 or 4 rings), wherein at least one ring is aromatic and wherein the other rings may be aromatic or non-aromatic. Such multiple fused ring systems are optionally substituted with one or more (e.g., 1, 2 or 3) oxo groups on any carbon ring portion of the multiple fused ring system. When valence requirements permit, the rings of the multiple fused ring system may be connected to each other by fusion, spiro and bridge bonds. It should be understood that the point of attachment of the polyfused ring system as defined above may be at any position of the aromatic ring. Non-limiting examples of aryl include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, etc.

[0055] As used herein, the term "heteroaryl" refers to a single aromatic ring having at least one atom other than carbon in the ring, where these atoms are selected from the group consisting of oxygen, nitrogen, and sulfur; "heteroaryl" also includes polyfused ring systems having at least one such aromatic ring, which polyfused ring systems are further described below. Thus, "heteroaryl" includes a single aromatic ring having from about 1 to 6 carbon atoms and from about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. If the ring is aromatic, the sulfur and nitrogen atoms can also be in oxidized forms. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. "Heteroaryl" also includes polyfused ring systems (e.g., ring systems containing 2, 3, or 4 rings), where as defined above, the heteroaryl is fused to one or more rings selected from heteroaryl (forming, for example, naphthyridinyl such as 1,8-naphthyridinyl), heterocycle (forming, for example, 1,2,3,4-tetrahydronaphthyridinyl such as 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (forming, for example, 5,6,7,8-tetrahydroquinolinyl), and aryl (forming, for example, indazolyl) to form a polyfused ring system. Thus, heteroaryl (single aromatic ring or polyfused ring system) has from about 1 - 20 carbon atoms and from about 1 - 6 heteroatoms within the heteroaryl ring. Heteroaryl (single aromatic ring or multiple fused ring systems) can also have from about 5 to 12 or from about 5 to 10 members within the heteroaryl ring. The multiple fused ring systems can optionally be substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic moieties of the fused rings. When valence requirements permit, the rings of the multiple fused ring systems can be connected to each other by fusion, spiro, and bridging bonds. It should be understood that the individual rings of the multiple fused ring systems can be connected to each other in any order. It should also be understood that the point of attachment of the multiple fused ring systems (as defined above for heteroaryl) can be at any position of the heteroaryl ring. It should also be understood that the point of attachment of the heteroaryl or heteroaryl multiple fused ring systems can 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, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, thianthrenyl, pyrrolo[2,3-b]pyridinyl, quinazolin-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole, and 3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole. In one embodiment, the term "heteroaryl" refers to a single aromatic ring containing at least one heteroatom. For example, the term includes 5- and 6-membered monocyclic aromatic rings that include one or more heteroatoms. Non-limiting examples of heteroaryl include, but are not limited to, pyridyl, furyl, thiazole, pyrimidine, oxazole, and thiadiazole.

[0056] When used alone or as part of a substituent, the term "heterocycloalkyl" refers to any three- to twelve-membered monocyclic or polycyclic saturated ring structure containing at least one heteroatom selected from the group consisting of: O, N, P, B, and S. The heterocycloalkyls of the present disclosure include monocyclic groups, as well as polycyclic groups such as bicyclic and tricyclic groups. In those embodiments having at least one polycyclic heterocycloalkyl, the cyclic groups may share a common atom (i.e., spiro). In other embodiments having at least one polycyclic heterocycloalkyl, the cyclic groups share two common atoms (e.g., fused or bridged). The term -C3-C6 heterocycloalkyl refers to a heterocycloalkyl having between three and six carbon ring atoms. The heterocycloalkyl may be attached at any heteroatom or carbon atom of the group such that the resulting structure is stable. Examples of heterocycloalkyls include, but are not limited to, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, tetrahydrofuryl, tetrahydropyranyl, piperazinyl, azepanyl, diazepanyl, oxepanyl, dioxepanyl, azocanyl, diazocanyl, oxocanyl, dioxocanyl, azaspiro[2.2]pentyl, oxaazaspiro[3.3]heptyl, oxaspiro[3.3]heptyl, dioxaspiro[3.3]heptyl, 3-azabicyclo[3.1.0]hexyl and the like. In some embodiments, the heterocycloalkyls of the present disclosure are optionally substituted. Unless otherwise indicated, in those embodiments in which the heterocycloalkyl is substituted, the heterocycloalkyl may be substituted with 1, 2, or 3 substituents independently selected from: -OH, -CN, amino, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -OC(O)NH(C1-C6 alkyl), -OC(O)N(C1-C6 alkyl)2, -S(O)2NH(C1-C6 alkyl), and -S(O)2N(C1-C6 alkyl)2. In other embodiments, the heterocycloalkyl is optionally substituted with 1-6 groups selected from: D, halogen, -OH, -CN, -OR a , -SR a , -NRa R d or NR c R d ; or the heterocycloalkyl is optionally substituted with one or more R f groups.

[0057] As used herein, the term "heterocycloalkenyl", when used alone or as part of a substituent, refers to any three- to twelve-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. The heterocycloalkenyls of the present disclosure include monocyclic groups, as well as polycyclic groups such as bicyclic groups and tricyclic groups. In those embodiments having at least one polycyclic heterocycloalkenyl, the cyclic groups may share a common atom (i.e., spiro). In other embodiments having at least one polycyclic heterocycloalkenyl, the cyclic groups share two common atoms (e.g., fused or bridged). The term -C3-C6 heterocycloalkenyl refers to a heterocycloalkenyl having between three and six carbon atoms. The heterocycloalkenyl may be attached at any heteroatom or carbon atom of the partially saturated ring such that the resulting structure is stable. The heterocycloalkenyl includes groups in which the partially saturated ring is fused to an aryl group, such as isoindoline, , or in which the partially saturated ring is fused to a heteroaryl group, such as 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, . In some embodiments, the heterocycloalkenyls of the present disclosure are optionally substituted. Unless otherwise indicated, in those embodiments in which the heterocycloalkenyl is substituted, the heterocycloalkenyl may be substituted with 1, 2, or 3 substituents independently selected from: -OH, -CN, amino, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -OC(O)NH(C1-C6 alkyl), -OC(O)N(C1-C6 alkyl)2, -S(O)2NH(C1-C6 alkyl), and -S(O ) 2N(C1-C6 alkyl)2. In other embodiments, the heterocycloalkenyl is optionally substituted with 1-6 groups selected from: D, halogen, -OH, -CN, -OR a , -SR a , -NR a R d or NR c R d ; or the heterocycloalkenyl is optionally substituted with one or more R f groups.

[0058] As used herein, the phrase "one or more R f groups" means including 1, 2, 3, 4, 5, 6, 7, or 8 Rf group. In some embodiments, "one or more R f groups" means including 1 R f group. In some embodiments, "one or more R f groups" means including at most 2 R f groups. In some embodiments, "one or more R f groups" means including at most 3 R f groups. In some embodiments, "one or more R f groups" means including at most 4 R f groups. In some embodiments, "one or more R f groups" means including at most 5 R f groups. In some embodiments, "one or more R f groups" means including at most 6 R f groups. In some embodiments, "one or more R f groups" means including at most 7 R f groups. In some embodiments, "one or more R f groups" means including at most 8 R f groups.

[0059] As used herein, the term "heteroatom" means including oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), boron (B), and silicon (Si). Where feasible, nitrogen and sulfur may be in oxidized forms.

[0060] As used herein, the term "chiral" refers to a molecule having the property that its mirror image is non-superimposable, while the term "achiral" refers to a molecule that is superimposable on its mirror image.

[0061] As used herein, the term "stereoisomer" refers to a compound having the same chemical composition but a different arrangement of atoms or groups in space, for example, enantiomers, diastereomers, tautomers.

[0062] Throughout this specification, the terms "patient" or "subject" are used to describe an animal, preferably a human or a domesticated animal, to which treatment with a composition according to the present disclosure is provided, including prophylactic treatment. For the treatment of those infections, conditions, or disease states specific to a particular animal (e.g., a human patient), the term patient refers to that particular animal, including domesticated animals such as dogs or cats or farm animals such as horses, cows, sheep, etc. Generally, in the present disclosure, unless otherwise specified or implied by the context in which the term is used, the term patient refers to a human patient.

[0063] The term "effective" is used to describe the amount of a compound, composition or component that, when used in the context of its intended use, achieves the intended result. The term effective encompasses all other effective amount or effective concentration terms otherwise described or used in this application.

[0064] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a State government or the corresponding agency in a country other than the United States, or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeias for use in animals (e.g., in humans).

[0065] "Pharmaceutically acceptable salt" refers to a salt of a compound of the present disclosure that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Specifically, such salts are non-toxic and can be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or formed from 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, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion or an aluminum ion); or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. By way of example only, salts further include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and when the compound contains a basic functional group, include salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate, etc.

[0066] "Pharmaceutically acceptable excipient" means a non-toxic, biologically tolerable and otherwise biologically suitable substance for administration to a subject, such as an inert substance, that is added to a pharmacological composition or otherwise used as an agent, carrier or diluent to facilitate the administration of the medicament and is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and various types of starches, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol.

[0067] "Solvate" means the physical association of a compound of Formula I with one or more solvent molecules.

[0068] In one embodiment, "treating" or "treatment" of any disease or disorder means ameliorating the disease or disorder (i.e., arresting or reducing the development of at least one clinical symptom of the disease or its clinical symptoms). In another embodiment, "treating" or "treatment" means ameliorating at least one physical parameter that may not be discernible by a subject. In yet another embodiment, "treating" or "treatment" means modulating the disease or disorder physically (e.g., stabilization of an indiscernible symptom), physiologically (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treatment" means delaying the onset of the disease or disorder.

[0069] In one aspect, the present disclosure relates to a compound of Formula (I):

[0070] (I)

[0071] or a pharmaceutically acceptable salt thereof; wherein

[0072] R1 is halo, C 1-6 alkyl or C 1-6 haloalkyl;

[0073] Each R2 is independently H, D or F;

[0074] Each R3 is independently H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 heteroalkyl or C 3-6 cycloalkyl;

[0075] n is 1, 2 or 3;

[0076] m is 1, 2, 3 or 4;

[0077] R4 is H, D, C 1-6 alkyl, C 1-6 alkoxyalkyl, C 3-6 cycloalkyl or C 1-6 haloalkyl;

[0078] R5 is H, D or F;

[0079] L1 is a bond, O, S, S(O), SO2, NR3, C(R3)2 or CO;

[0080] L2 is a bond, O, S, S(O), SO2, NR3, C(R3)2 or CO;

[0081] Ring A1 is a 6-membered aryl or 5-6-membered heteroaryl;

[0082] Ring A2 is a 3-7-membered cycloalkyl or 4-7-membered heterocycloalkyl;

[0083] X1 is CH2, CO, CH=CH (when X2 = CO) or N=CH (when X2 = CO);

[0084] X2 is CH2, CO, CH=CH (when X1 = CO) or N=CH (when X1 = CO);

[0085] wherein the alkyl, the haloalkyl, the cycloalkyl, the alkoxyalkyl, the aryl, the heteroaryl or the heterocycloalkyl is optionally substituted by one or more R f groups;

[0086] Each Rf independently is D, oxo, halogen, C1-C8 alkoxy, C1-C8 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)2NR 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)2R 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 optionally substituted by 1-6 groups selected from: D, halogen, -OH, -CN, -OR a 、 -SR a 、 -NR a R d or NR c R d ;

[0087] Each R a independently is 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)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;

[0088] Each Rb 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;

[0089] Each R c or R d independently is H, D, -C1-C 10 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OC1-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;

[0090] or R c and R d together with the atoms to which both are attached form a monocyclic or polycyclic heterocycloalkyl or a monocyclic or polycyclic heterocycloalkenyl.

[0091] In some embodiments, R in formula I 1 is halo, C 1-6 alkyl or C 1-6 haloalkyl. In some embodiments, R in formula I 1 is halo. In some embodiments, R in formula I 1 is C 1-6 alkyl. In some embodiments, R in formula I 1 is C 1-6 haloalkyl.

[0092] In other embodiments, R in formula I 1 is F. In other embodiments, R in formula I 1 is Cl. In other embodiments, R in formula I 1 is methyl.

[0093] In some embodiments, each R2 in formula I is independently H, D or F. In some embodiments, each R2 in formula I is H. In some embodiments, each R2 in formula I is D. In some embodiments, each R2 in formula I is F.

[0094] In other embodiments, at least one R2 in formula I is H. In other embodiments, at least one R2 in formula I is D. In other embodiments, at least one R2 in formula I is F.

[0095] 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 still other embodiments, n in formula (I) is 3.

[0096] In some embodiments, each R3 in formula I is independently H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 heterocycloalkyl, or C 3-6 cycloalkyl. In some embodiments, each R3 in formula I is H. In some embodiments, each R3 in formula I is D. In some embodiments, each R3 in formula I is C 1-6 alkyl. In some embodiments, each R3 in formula I is C 1-6 haloalkyl. In some embodiments, each R3 in formula I is C 3-6 heterocycloalkyl. In some embodiments, each R3 in formula I is C 3-6 cycloalkyl.

[0097] In other embodiments, at least one R3 in formula I is H. In other embodiments, at least one R3 in formula I is D. In other embodiments, at least one R3 in formula I is C 1-6 alkyl. In other embodiments, at least one R3 in formula I is haloalkyl. In other embodiments, at least one R3 in formula I is C 3-6 cycloalkyl.

[0098] 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.

[0099] In some embodiments, R4 in formula I is independently H, D, C 1-6 alkyl, C 1-6 alkoxyalkyl, haloalkyl, or C 3-6 cycloalkyl. In some embodiments, R4 in formula I is H. In some embodiments, R4 in formula I is D. In other embodiments, R4 in formula I is C 1-6 alkyl. In other embodiments, R4 in formula I is C 1-6 alkoxyalkyl. In other embodiments, R4 in formula I is C 1-6 haloalkyl. In still other embodiments, R4 in formula I is C 3-6 cycloalkyl.

[0100] In some embodiments, each of R5 in Formula I is independently H, D, or F. In some embodiments, R5 in Formula I is H. In other embodiments, R5 in Formula I is D. In other embodiments, R5 in Formula I is F.

[0101] 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.

[0102] 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.

[0103] In some embodiments, ring A1 in Formula (I) is a 6-membered aryl or a 5-6-membered heteroaryl. In some embodiments, ring A1 in Formula (I) is a 6-membered aryl. In some embodiments, ring A1 in Formula (I) is phenyl. In other embodiments, ring A1 is a 5-6-membered heteroaryl. In other embodiments, ring A1 is a pyridine group. In other embodiments, ring A1 is a pyrimidine group.

[0104] In some embodiments, ring A2 in Formula (I) is a 3-7-membered cycloalkyl or a 4-7-membered heterocycloalkyl. In some embodiments, ring A2 in Formula (I) is a 3-7-membered cycloalkyl. In some embodiments, ring A2 in Formula (I) is cyclohexyl. In some embodiments, ring A2 is a 4-7-membered heterocycloalkyl. In some embodiments, ring A2 in Formula (I) is piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, azacyclohexyl, or azabicyclohexyl.

[0105] In some embodiments, ring A2 in formula (I) is piperazinyl. In some embodiments, ring A2 in formula (I) is morpholinyl. In other embodiments, ring A2 in formula (I) is piperidinyl. In other embodiments, ring A2 in formula (I) is pyrrolidinyl. In still other embodiments, ring A2 in formula (I) is azetidinyl. In still other embodiments, ring A2 in formula (I) is azabicyclohexyl.

[0106] In some embodiments, X1 in formula (I) is CH2CO, 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).

[0107] In some embodiments, X2 in formula (I) is CH2CO, 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).

[0108] In some embodiments, each in formula I Rf is independently D, oxo, halogen, C1-C8 alkoxy, C1-C8 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)2NR 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)2R 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 optionally substituted with 1-6 groups selected from: D, halogen, -OH, -CN, -OR a , -SR a , -NR a R d or NR c R d .

[0109] In some embodiments, at least one R in Formula I f is D. In some embodiments, at least one R in Formula I f is oxo. In some embodiments, at least one R in Formula I f is halogen. In some embodiments, at least one R in Formula I f is C1-C8 alkoxy. In some embodiments, at least one R in Formula I f is C1-C8 alkyl. In some embodiments, the C1-C8 alkyl is optionally substituted with 1-6 groups 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 in Formula I f is haloalkyl. In some embodiments, at least one R in Formula I f is -OH. In some embodiments, R in Formula I f is -CN. In some embodiments, at least one R in Formula I f is -NO2. In some embodiments, at least one R in Formula I fis a C2-C6 alkenyl. In some embodiments, at least one R in formula I f is a C2-C6 alkynyl. In some embodiments, at least one R in formula I f is C 6-10 aryl. In some embodiments, at least one R in formula I f is C 5-12 heteroaryl. In some embodiments, at least one R in formula I f is C 3-8 cycloalkyl. In other embodiments, at least one R in formula I f is C 3-8 cycloalkenyl. In other embodiments, at least one R in formula I f is C 3-8 heterocycloalkyl. In other embodiments, at least one R in formula I f is C 3-8 heterocycloalkenyl. In other embodiments, at least one R in formula I f is -OR a . In other embodiments, at least one R in formula I f is -SR a . In other embodiments, at least one R in formula I f is -NR c R d . In other embodiments, at least one R in formula I f is -NR a R c . In other embodiments, at least one R in formula I f is -C(O)R b . In other embodiments, at least one R in formula I f is -OC(O)R b . In other embodiments, at least one R in formula I f is -C(O)OR b . In other embodiments, at least one R in formula I f is -C(O)NR c R d . In still other embodiments, at least one R in formula I f is -S(O)R b . In still other embodiments, at least one R in formula I f is -S(O)2NR c R d . In still other embodiments, at least one R in formula I f is -S(O)(=NR b )R b . In still other embodiments, at least one R in formula If is -SF5. In still other embodiments, at least one R in Formula I f is -P(O)R b R b . In still other embodiments, at least one R in Formula I f is -P(O)(OR b )(OR b ). In still other embodiments, at least one R in Formula I f is -B(OR c )(OR d ). In still other embodiments, at least one R in Formula I f is -S(O)2R b . In still other embodiments, at least one R in Formula I f is -C(O)NR b OR b . In still other embodiments, at least one R in Formula I f is -S(O)2OR b . In still other embodiments, at least one R in Formula I f is -OS(O)2OR b . In still other embodiments, at least one R in Formula I f is -OPO(OR b )(OR b ).

[0110] In some embodiments, each R in Formula I a is 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)OR c OR b , -S(O)R b , -S(O)NR c R d , -S(O)2R b , -S(O)2NR c Rd 、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.

[0111] In some embodiments, at least one R in formula I a is H. In some embodiments, at least one R in formula I a is D. In some embodiments, at least one R in formula I a is -C(O)R b . In some embodiments, at least one R in formula I a is -C(O)OR c . In some embodiments, at least one R in formula I a is -C(O)NR c R d . In some embodiments, at least one R in formula I a is -C(=NR b )NR b R c . In some embodiments, at least one R in formula I a is C(=NOR b )NR b R c . In some embodiments, at least one R in formula I a is -C(=NCN)NR b R c .

[0112] In other embodiments, at least one R in 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)2NR c R d 、SiR b 3 etc. In still other embodiments, at least one R in formula Ia 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, etc.

[0113] In some embodiments, each R in formula I b is 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.

[0114] In some embodiments, at least one R in formula I b is H. In some embodiments, at least one R in formula I b is D. In some embodiments, at least one R in formula I b is -C1-C6 alkyl. In some embodiments, at least one R in formula I b is -C2-C6 alkenyl. In some embodiments, at least one R in formula I b is -C2-C6 alkynyl. In other embodiments, at least one R in formula I b is C 6-10 aryl. In other embodiments, at least one R in formula I b is C 3-8 cycloalkyl. In other embodiments, at least one R in formula I b is C 3-8 cycloalkenyl. In other embodiments, at least one R in formula I b is C 5-12 heteroaryl. In other embodiments, at least one R in formula I b is C 3-8 heterocycloalkyl. In other embodiments, at least one R in formula I b is C 3-8 heterocycloalkenyl.

[0115] In some embodiments, each R or R in formula I c or R d is independently H, D, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, C6-10 Aryl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 5-12 Heteroaryl, C 3-8 Heterocycloalkyl or C 3-8 Heterocycloalkenyl.

[0116] In some embodiments, R c or R d in Formula I is H. In some embodiments, R c or R d in Formula I is D. In some embodiments, R c or R d in Formula I is -C1-C 10 alkyl. In some embodiments, R c or R d in Formula I is -C2-C6 alkenyl. In some embodiments, R c or R d in Formula I is -C2-C6 alkynyl. In other embodiments, R c or R d in Formula I is -OC1-C6 alkyl. In other embodiments, R c or R d in Formula I is -O-cycloalkyl. In other embodiments, R c or R d in Formula I is C 6-10 aryl. In other embodiments, R c or R d in Formula I is C 3-8 cycloalkyl. In other embodiments, R c or R d in Formula I is C 3-8 cycloalkenyl. In other embodiments, R c or R d in Formula I is C 5-12 heteroaryl. In other embodiments, R c or R d in Formula I is C 3-8 heterocycloalkyl. In other embodiments, R c or R d in Formula I is C 3-8 heterocycloalkenyl.

[0117] In still other embodiments, R c and R d together with the atom to which both are attached form a monocyclic or polycyclic heterocycloalkyl or a monocyclic or polycyclic heterocycloalkenyl. In still other embodiments, R c and R dForm a monocyclic heterocycloalkyl. In still other embodiments, R in formula I c and R d Form a polycyclic heterocycloalkyl. In still other embodiments, R in formula I c and R d Form a monocyclic heteroalkenyl. In still other embodiments, R in formula I c and R d Form a polycyclic heteroalkenyl.

[0118] 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.

[0119] In some embodiments, the compound of formula (I) is represented by the compounds of formula IIa and formula IIb:

[0120] (IIa)

[0121] (IIb)

[0122] Or a pharmaceutically acceptable salt thereof; wherein each R1, R2, R4, L1, ring A1, L2, ring A2, X1 and X2 are defined above with respect to formula (I).

[0123] In some embodiments, the compound of formula (I) is represented by the compounds of formula IIIa and formula IIIb:

[0124] (IIIa)

[0125] (IIIb)

[0126] Or a pharmaceutically acceptable salt thereof; wherein each R1, R2, R4, L1, L2, ring A2, X1 and X2 are defined above with respect to formula (I);

[0127] Each Z is independently N or CR6; wherein R6 is the same as Rf.

[0128] In some embodiments of formula IIIa or formula IIIb, each R6 is independently H, D, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 3-6 cycloalkyl.

[0129] In some embodiments of formula IIIa or formula IIIb, each R6 is independently H, D, halo, -CN, C1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 3-6 cycloalkyl.

[0130] 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 Zs 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 Zs in Formula IIIa or Formula IIIb are CR6.

[0131] In some embodiments, each R6 in 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 cycloalkyl. In some embodiments, each R6 in Formula IIIa or Formula IIIb is H. In some embodiments, each R6 in Formula IIIa or Formula IIIb is D. In some embodiments, each R6 in Formula IIIa or Formula IIIb is halo. In some embodiments, each R6 in Formula IIIa or Formula IIIb is -CN. In other embodiments, each R6 in Formula IIIa or Formula IIIb is C 1-6 alkyl. In other embodiments, each R6 in Formula IIIa or Formula IIIb is C 1-6 alkoxy. In other embodiments, each R6 in Formula IIIa or Formula IIIb is C 1-6 haloalkyl. In other embodiments, each R6 in Formula IIIa or Formula IIIb is C 1-6 haloalkoxy. In other embodiments, each R6 in Formula IIIa or Formula IIIb is C 3-6 cycloalkyl.

[0132] In other embodiments, at least one R6 in Formula IIIa or Formula IIIb is H. In other embodiments, at least one R6 in Formula IIIa or Formula IIIb is D. In other embodiments, at least one R6 in Formula IIIa or Formula IIIb is halo. In other embodiments, at least one R6 in Formula IIIa or Formula IIIb is -CN. In other embodiments, at least one R6 in Formula IIIa or Formula IIIb is C 1-6Alkyl. In other embodiments, at least one R6 in Formula IIIa or Formula IIIb is C 1-6 Haloalkyl. In other embodiments, at least one R6 in Formula IIIa or Formula IIIb is C 3-6 Cycloalkyl.

[0133] In some embodiments, the compound of formula (I) is represented by a compound of formula IVa or formula IVb

[0134] (IVa)

[0135] (IVb)

[0136] or a pharmaceutically acceptable salt thereof; wherein each R1, R2, R4, L1, L2, X1 and X2 is defined above with respect to formula (I); each Z and R6 is defined above with respect to formula IIIa or formula IIIb; and Z1 is N or CR6.

[0137] In some embodiments, Z1 in formula IVa or formula IVb is N or CR6. In some embodiments, Z1 in formula IVa or formula IVb is N. In some embodiments, Z1 in formula IVa or formula IVb is CR6.

[0138] In some embodiments, the compound of formula (I) is represented by a compound of formula Va or formula Vb

[0139] (Va)

[0140] (Vb)

[0141] or a pharmaceutically acceptable salt thereof; wherein each R1, R2, R4 and L1 is defined above with respect to formula (I); each Z and R6 is defined above with respect to formula IIIa or formula IIIb; and Z1 is defined above with respect to formula IVa or formula IVb.

[0142] In some embodiments, the compound of formula (I) is represented by a compound of formula VIa or formula VIb

[0143] (VIa)

[0144] (VIb)

[0145] or a pharmaceutically acceptable salt thereof; wherein each R1, R2 and R4 is defined above with respect to formula (I); each Z and R6 is defined above with respect to formula IIIa or formula IIIb; and Z1 is defined above with respect to formula VIa or formula VIb.

[0146] In some embodiments, the compound of formula (I) is represented by a compound of formula VIIa or formula VIIb

[0147] (VIIa)

[0148] (VIIb)

[0149] or a pharmaceutically acceptable salt thereof; wherein each R2, R4 and L1 is defined above with respect to formula (I); each Z and R6 is defined above with respect to formula IIIa or formula IIIb; and Z1 is defined above with respect to formula VIa or formula VIb.

[0150] In still other embodiments, the compound of formula (I) is:[[]]

[0151] 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;

[0152] 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)-3-methylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0153] 3-(6-(4-((5-(((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-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0154] 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)-3-fluorobenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0155] 3-(6-(4-(4-(((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)oxy)benzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0156] 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;

[0157] 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)-2-methylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0158] 3-(6-(4-(4-(((6aR,8R)-2-(3-chloro-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;

[0159] 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)-2,5-dimethylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0160] 3-(6-(4-(4-(((6aR,8R)-2-(3-chloro-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;

[0161] 3-(6-(4-(4-(((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)oxy)-2-methylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0162] 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)-2-methoxybenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0163] 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)-2-fluorobenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0164] 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)-3-isopropylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0165] 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)-2-(trifluoromethyl)benzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0166] 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)-2-isopropylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0167] 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)-2,6-dimethylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0168] 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)-2,3-dimethylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0169] 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)-2-methylbenzyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0170] 3-(6-(4-(4-(((6aR,8R)-2-(2-hydroxy-3-methylphenyl)-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;

[0171] 3-(6-(4-(4-(((6aR,8R)-2-(3-chloro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[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;

[0172] 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;

[0173] 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;

[0174] 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;

[0175] (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;

[0176] 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;

[0177] 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;

[0178] (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;

[0179] (S)-3-(6-(1-((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)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0180] (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)oxy)-2-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0181] 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)-5-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0182] 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;

[0183] 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;

[0184] 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]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0185] 3-(6-(4-((6-(((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)(methyl)amino)pyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0186] 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;

[0187] 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;

[0188] (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)sulfanyl)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0189] 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;

[0190] or a pharmaceutically acceptable salt thereof.

[0191] In yet other embodiments, the compound of formula (I) is:

[0192] 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;

[0193] 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;

[0194] 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;

[0195] (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;

[0196] (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;

[0197] (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;

[0198] (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;

[0199] (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;

[0200] (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;

[0201] (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;

[0202] 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;

[0203] 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;

[0204] 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;

[0205] 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;

[0206] 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;

[0207] 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;

[0208] 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;

[0209] (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;

[0210] (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;

[0211] 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;

[0212] 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)sulfanyl)-4-methylpyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0213] 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;

[0214] 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;

[0215] 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;

[0216] (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;

[0217] (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;

[0218] (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;

[0219] (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;

[0220] (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;

[0221] (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;

[0222] 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;

[0223] (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;

[0224] (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-fluoropyridin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0225] (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;

[0226] (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;

[0227] (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;

[0228] 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;

[0229] (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;

[0230] (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;

[0231] (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)isatin-2-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

[0232] (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;

[0233] (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;

[0234] (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;

[0235] (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;

[0236] 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;

[0237] 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;

[0238] (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;

[0239] (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;

[0240] 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;

[0241] (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;

[0242] (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;

[0243] (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;

[0244] (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;

[0245] (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;

[0246] (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;

[0247] (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;

[0248] (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;

[0249] (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;

[0250] (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;

[0251] (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;

[0252] (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;

[0253] (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;

[0254] (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;

[0255] (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;

[0256] (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;

[0257] 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;

[0258] 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;

[0259] or a pharmaceutically acceptable salt thereof.

[0260] It will be apparent that the compounds of Formula I (including all subgenera described herein) can have multiple stereocenters. Accordingly, there are multiple stereoisomers (enantiomers and diastereomers) of the compounds of Formula I (and the subgenera described herein). The present disclosure contemplates and encompasses each stereoisomer of any compound of Formula I (and the subgenera described herein), as well as mixtures of said stereoisomers.

[0261] Pharmaceutically acceptable salts and solvates of the compounds of Formula I (including all subgenera described herein) are also within the scope of the present disclosure.

[0262] The present disclosure also contemplates isotopically labeled variants of the compounds of Formula I (including all subgenera described herein).

[0263] Pharmaceutical Compositions and Methods of Administration

[0264] The pharmaceutical compositions of the present invention are generally formulated to provide a therapeutically effective amount of a compound of the present disclosure in the form of an active ingredient or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. When needed, the pharmaceutical compositions contain a pharmaceutically acceptable salt and / or coordination complex thereof and one or more pharmaceutically acceptable excipients, carriers (including inert solid diluents and fillers), diluents (including sterile aqueous solutions and various organic solvents), permeation enhancers, solubilizers and adjuvants.

[0265] The pharmaceutical compositions of the present invention can be administered alone or in combination with one or more other agents, which are also generally administered in the form of pharmaceutical compositions. When needed, one or more compounds of the present invention and the other agents can be combined into a formulation, or the two components can be formulated into separate formulations for separate or simultaneous combined use.

[0266] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical composition of the present invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% (or a number within the range defined by any two of the above and including any two of the above) w / w, w / v or v / v.

[0267] In some embodiments, the concentration of one or more compounds of the present invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 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 the range defined by any two of the above and including any two of the above) w / w, w / v or v / v.

[0268] In some embodiments, the concentration of one or more compounds of the present invention is in the range of about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10% w / w, w / v or v / v.

[0269] In some embodiments, the concentration of one or more compounds of the present invention is in the range of about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w / w, w / v or v / v.

[0270] In some embodiments, the amount of one or more compounds of the present invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 or 0.0001 g (or a number within the range defined by any two of the above numbers and including any two of the above numbers).

[0271] In some embodiments, the amount of one or more compounds of the present invention is greater than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g or 10 g (or a number within the range defined by any two of the above and including any two of the above).

[0272] 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.

[0273] The compounds according to the present invention are effective in a wide range of doses. For example, when treating adults, doses 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 doses that can be used. An exemplary dose is 10 to 30 mg per day. The exact dose will depend on the route of administration, the form of compound administration, the subject to be treated, the weight of the subject to be treated, and the preference and experience of the attending physician.

[0274] The pharmaceutical compositions of the present invention generally contain the active ingredient of the present invention (e.g., the compounds disclosed herein) 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.

[0275] Non-limiting exemplary pharmaceutical compositions and methods for their preparation are described below.

[0276] Pharmaceutical Compositions for Oral Administration

[0277] In some embodiments, the present invention provides a pharmaceutical composition for oral administration, which contains a compound of the present invention and a pharmaceutical excipient suitable for oral administration.

[0278] In some embodiments, the present invention provides a solid pharmaceutical composition for oral administration, which contains: (i) an effective amount of a compound of the present invention; optionally (ii) an effective amount of a second medicament; and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further contains: (iv) an effective amount of a third medicament.

[0279] In some embodiments, the pharmaceutical composition can be a liquid pharmaceutical composition suitable for oral consumption. The pharmaceutical compositions of the present invention suitable for oral administration can be presented in discrete dosage forms, such as capsules, cachets, or tablets, or liquid or aerosol sprays, solutions, or suspensions in aqueous or non-aqueous liquids, oil-in-water emulsions or water-in-oil liquid emulsions, each containing a predetermined amount of the active ingredient in the form of a powder or granules. Such dosage forms can be prepared by any pharmaceutical method, but all methods include the step of associating the active ingredient with a carrier, which constitutes one or more essential ingredients. Generally, the composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired presentation form. 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 dispersants. Molded tablets can be prepared by molding in a suitable machine a mixture of powdered compounds moistened with an inert liquid diluent.

[0280] The present invention further encompasses anhydrous pharmaceutical compositions and dosage forms that contain an active ingredient, as water can promote the degradation of some compounds. For example, in the pharmaceutical field, water (e.g., 5%) can be added as a means to simulate long-term storage to determine the characteristics of a formulation over time, such as shelf life or stability. The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-moisture ingredients and low-moisture or low-humidity conditions. If substantial contact with moisture and / or humidity is expected during manufacturing, packaging, and / or storage, the pharmaceutical compositions and dosage forms of the present invention containing lactose can be made water-free. The anhydrous pharmaceutical compositions can be prepared and stored in a manner that maintains their anhydrous nature. Thus, the anhydrous compositions can be packaged using materials known to prevent exposure to water such that the compositions can be included in a suitable, predefined kit. Examples of suitable packaging include, but are not limited to, sealed foils, plastics, etc., unit-dose containers, blister packs, and strip packs.

[0281] According to conventional pharmaceutical compounding techniques, the active ingredient can be intimately mixed with a pharmaceutical carrier. The carrier can take various forms depending on the desired form of preparation for administration. When preparing compositions for oral dosage forms, in the case of oral liquid preparations such as suspensions, solutions, and elixirs, or aerosols, any common pharmaceutical medium can be used as the carrier, such as water, ethylene glycol, oils, alcohols, flavoring agents, preservatives, coloring agents, etc.; or in the case of oral solid preparations, carriers such as starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used, and lactose is not used in some embodiments. For example, in the case of solid oral preparations, suitable carriers include powders, capsules, and tablets. If desired, the tablets can be coated by standard aqueous or non-aqueous techniques.

[0282] 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 arabic, 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, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.

[0283] 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., granular or powdered), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0284] Disintegrants can be used in the compositions of the present invention to provide tablets that disintegrate upon exposure to an aqueous environment. Too much disintegrant may result in tablets that disintegrate in the bottle. Too little disintegrant may be insufficient to cause disintegration and may thus alter the rate and extent of release of one or more active ingredients from the dosage form. Thus, an amount of disintegrant sufficient (without unfavorably altering the release of one or more active ingredients either too little or too much) can be used to form dosage forms of the compounds disclosed herein. The amount of disintegrant used can vary based on the formulation type and mode of administration and can be readily discerned by one of ordinary skill in the art. About 0.5 to about 15% by weight of disintegrant or about 1 to about 5% by weight of disintegrant can be used in the pharmaceutical composition. Disintegrants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, sodium carboxymethylcellulose cross-linked, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other alginates, other celluloses, gums, or mixtures thereof.

[0285] 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 diols, 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, synthetic silica gels, coagulated aerosols of synthetic silica, or mixtures thereof. Optionally, the lubricant can be added in an amount less than about 1% by weight of the pharmaceutical composition.

[0286] When an aqueous suspension and / or elixir is required for oral administration, the active ingredient therein can be mixed with various sweetening or flavoring agents, coloring agents or dyes, and (if desired) emulsifying and / or suspending agents, and such diluents as water, ethanol, propylene glycol, glycerin, and various combinations thereof.

[0287] Tablets can be uncoated or can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can also be presented in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or in the form of soft gelatin capsules wherein the active ingredient is mixed with a water or oil medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0288] Surfactants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, mixtures of hydrophilic surfactants can be employed, mixtures of lipophilic surfactants can be employed, or mixtures of at least one hydrophilic surfactant and at least one lipophilic surfactant can be employed.

[0289] The HLB value of suitable hydrophilic surfactants can generally be at least 10, while the HLB value of suitable lipophilic surfactants can generally be or less than about 10. The empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values are more lipophilic or hydrophobic and have greater solubility in oil, while surfactants with higher HLB values are more hydrophilic and have greater solubility in aqueous solutions.

[0290] Hydrophilic surfactants are generally considered to be those compounds with 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 with an HLB value equal to or less than about 10. However, the HLB value of a surfactant is only a rough guide generally used to achieve the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0291] Hydrophilic surfactants can be ionic or nonionic surfactants. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidates; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glycerol ester derivatives of amino acids, oligopeptides, and polypeptides; lecithin and hydrogenated lecithin; lysophosphatidylcholine and hydrogenated lysophosphatidylcholine; phospholipids and their derivatives; lysophospholipids and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; acyl lactates; mono- and di-acetylated tartaric acid esters of mono- and diglycerides; succinylated mono- and diglycerides; citric acid esters of mono- and diglycerides; and mixtures thereof.

[0292] Within the above groups, ionic surfactants include, for example: lecithin, lysophosphatidylcholine, phospholipids, lysophospholipids and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; acyl lactates; mono- and di-acetylated tartaric acid esters of mono- and diglycerides; succinylated mono- and diglycerides; citric acid esters of mono- and diglycerides; and mixtures thereof.

[0293] The ionic surfactant may be in the following ionized forms: lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, fatty acid lactate, stearoyl-2-lactylate, stearoyl lactate, succinylated monoglyceride, mono / diglyceride mono / diacetylated tartrate, mono / diglyceride citrate, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, dodecyl sulfate, tetradecyl sulfate, dioctyl sulfosuccinate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and their salts and mixtures.

[0294] The hydrophilic nonionic surfactant may include but is not limited to alkyl glucoside; alkyl maltoside; alkyl thioglucoside; polyethylene glycol glycerol laurate; polyoxyalkylene alkyl ether, such as polyethylene glycol alkyl ether; polyoxyalkylene alkyl phenol, such as polyethylene glycol alkyl phenol; polyoxyalkylene alkyl phenol fatty acid ester, such as polyethylene glycol fatty acid monoester and polyethylene glycol fatty acid diester; polyethylene glycol glycerol fatty acid ester; polyglycerol fatty acid ester; polyoxyalkylene sorbitan fatty acid ester, such as polyethylene glycol sorbitan fatty acid ester; hydrophilic transesterification products of polyols having at least one member selected from the group consisting of glyceride, vegetable oil, hydrogenated vegetable oil, fatty acid, and sterol; polyoxyethylene sterol, its derivatives and analogs; polyoxyethylated vitamins and their derivatives; polyoxyethylene-polyoxypropylene block copolymer; and their mixtures; polyethylene glycol sorbitan fatty acid ester and hydrophilic transesterification products of polyols having at least one member selected from the group consisting of triglyceride, vegetable oil, and hydrogenated vegetable oil. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or sugar.

[0295] Other hydrophilic nonionic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprylic / capric glycerides, PEG-8 caprylic / capric glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phytosterol, PEG-30 stigmasterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 dodecyl ether, POE-23 dodecyl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series, and poloxamer.

[0296] By way of example only, suitable lipophilic surfactants include: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylenated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of polyols having at least one member of the group consisting of glycerol esters, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or hydrophobic transesterification products of polyols having at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0297] In one embodiment, the composition may include solubilizers to ensure good solubilization and / or dissolution of the compounds of the present invention and to minimize precipitation of the compounds of the present invention. This is particularly important for compositions for non-oral use (e.g., injectable compositions). Solubilizers may also be added to increase the solubility of hydrophilic drugs and / or other components such as surfactants or to keep the composition as a stable or homogeneous solution or dispersion.

[0298] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols such as ethanol, isopropyl alcohol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butylene glycol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, epoxydiol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; polyethylene glycol ethers having an average molecular weight of from 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-alkylpyrrolidones, N-hydroxyalkylpyrrolidones, N-alkylpiperidones, N-alkylcaprolactams, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, triethyl acetylcitrate, tributyl acetylcitrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizers known in the art such as dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, monoglyceryl caprylate, diethylene glycol monoethyl ether and water.

[0299] Mixtures of solubilizers may also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, glycofurol, epoxydiol, propylene glycol and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethanol, PEG-400, glycofurol and propylene glycol.

[0300] 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 that can be readily determined by those skilled in the art. In some cases, it may be advantageous to include a solubilizer in an amount far exceeding the biologically acceptable amount, for example, to maximize the concentration of the drug, where excess solubilizer is removed using conventional techniques such as distillation or evaporation before the composition is administered to a subject. Thus, by weight of the combined weight of the drug and other excipients, the weight ratio of the solubilizer (if present) can be 10 wt%, 25 wt%, 50 wt%, 100 wt% or up to about 200 wt%. If desired, very small amounts of solubilizer can also be used, such as 5%, 2%, 1% or even less. Typically, the solubilizer can be present in an amount of from about 1 wt% to about 100 wt%, more typically from about 5 wt% to about 25 wt%.

[0301] The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, anti-adhesives, anti-foaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicifiers, flavoring agents, coloring agents, flavor enhancers, opacifying agents, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0302] Additionally, an acid or a base can be incorporated into the composition to facilitate processing, enhance stability, or achieve other purposes. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS), and the like. Also suitable are bases that are salts of pharmaceutically acceptable acids such as acetic acid, acrylic acid, adipic acid, alginic acid, methanesulfonic 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, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, mercaptoacetic acid, toluenesulfonic acid, uric acid, and the like. Salts of polyprotic acids such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation such as ammonium, alkali metal, alkaline earth metal, etc. Examples can include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0303] 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, hydroquinone sulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, mercaptoacetic acid, toluenesulfonic acid, uric acid, etc.

[0304] Pharmaceutical Compositions for Injection

[0305] In some embodiments, the present invention provides a pharmaceutical composition for injection, which contains the compound of the present invention and a pharmaceutically acceptable excipient suitable for injection. The components and amounts of the medicaments in the composition are as described herein.

[0306] Forms that can be incorporated into the novel compositions of the present invention for administration by injection include aqueous or oil suspensions or emulsions having sesame oil, corn oil, cottonseed oil or peanut oil, and elixirs, mannitol, dextrose or sterile aqueous solutions and similar pharmaceutical vehicles.

[0307] Aqueous solutions in saline are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc. (and suitable mixtures thereof), cyclodextrin derivatives and vegetable oils can also be used. Appropriate fluidity can be maintained, for example, by using coatings such as lecithin, by maintaining the required particle size in the case of dispersants, and by using surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents (for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.).

[0308] A sterile injectable solution is prepared by incorporating the compound of the present invention in the required amount, as needed, together with the various other ingredients enumerated above into a suitable solvent, and then filtering and sterilizing. Generally, a dispersion is prepared by incorporating the various sterilized active ingredients into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desirable preparation methods are vacuum drying and freeze-drying techniques, which produce powders of the active ingredients and any additional desired ingredients from their previously sterile-filtered solutions.

[0309] Pharmaceutical Compositions for Local (e.g., Transdermal) Delivery

[0310] In some embodiments, the present invention provides a pharmaceutical composition for transdermal delivery, which comprises the compound of the present invention and a pharmaceutically acceptable excipient suitable for transdermal delivery.

[0311] The compositions of the present invention can be formulated into preparations in solid, semi-solid or liquid form suitable for local or topical administration, such as gels, water-soluble colloids, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, DMSO-based solutions. Generally, carriers with higher density can provide a longer exposure area to the active ingredient. In contrast, solution formulations can expose the active ingredient more directly to the selected area.

[0312] The pharmaceutical composition may also contain a suitable solid or gel phase carrier or excipient, which is a compound that increases the permeability of the stratum corneum permeability barrier of the skin to the therapeutic molecule or aids in the delivery of the therapeutic molecule across the stratum corneum permeability barrier of the skin. There are many such permeation-enhancing molecules for those skilled in the art of topical formulation.

[0313] Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), diols (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.

[0314] Another exemplary formulation used in the method of the present invention employs a transdermal delivery device ("patch"). Such transdermal patches can be used to provide a continuous or discontinuous infusion of the compounds of the present invention in a controlled amount, with or without another agent.

[0315] The construction and use of transdermal patches for delivering agents are well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. Such patches can be constructed for continuous, pulsatile, or on-demand delivery of the agent.

[0316] Pharmaceutical Compositions for Inhalation

[0317] Compositions for inhalation or insufflation comprise solutions, suspensions, or mixtures thereof in pharmaceutically acceptable aqueous or organic solvents, and powders. The 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 to produce local or systemic effects. The compositions in preferably pharmaceutically acceptable solvents may be atomized by the use of inert gases. The atomized solution may be inhaled directly from the atomizing device, or the atomizing device may be attached to a facemask plug or intermittent positive pressure breathing machine. Solutions, suspensions, or powder compositions may be administered orally or nasally preferably from a device that delivers the formulation in a suitable manner.

[0318] Other Pharmaceutical Compositions

[0319] The pharmaceutical composition can also be prepared from the compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural or intrathecal administration. The preparation of such pharmaceutical compositions is well known in the art. See, for example, Anderson, Philip O.; Knoben, James E.; Troutman, William G editors, Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor editors, Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung editor, Basic and Clinical Pharmacology, Ninth Edition, McGraw-Hill, 20037ybg; Goodman and Gilman editors, The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw-Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Edition, Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all references are incorporated herein by reference in their entirety.

[0320] Administration of the compounds or pharmaceutical compositions of the present invention can be achieved by any method capable of delivering the compound to the site of action. These methods include oral route, duodenal route, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intracardiac, intraperitoneal or infusion), topical (e.g., transdermal application), rectal administration, local delivery via catheter or stent, or by inhalation. The compound can also be administered intraadipose or intrathecally.

[0321] In some embodiments, the compounds or pharmaceutical compositions of the present invention are administered by intravenous injection.

[0322] The amount of the compound administered will depend on the subject being treated, the severity of the condition or disorder, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. However, whether administered as a single dose or in divided doses, an effective dose is in the range of from about 0.001 to about 100 mg per kg body weight per day, preferably from about 1 to about 35 mg / kg / day. For a 70 kg person, this would correspond to from about 0.05 to 7 g / day, preferably from about 0.05 to about 2.5 g / day. In some cases, dose levels below the lower limit of the above range may be more than sufficient, while in other cases, additional larger doses may be employed without causing any harmful side effects, for example by dividing such larger doses into several smaller doses for administration throughout the day.

[0323] In some embodiments, the compounds of the invention are administered as a single dose.

[0324] Typically, such administration will be by injection, such as intravenous injection, for rapid introduction of the agent. However, other routes may be used as appropriate. A single dose of the compounds of the invention can also be used to treat acute conditions.

[0325] In some embodiments, the compounds of the invention are administered in multiple doses. Administration can be about once a day, twice a day, three times a day, four times a day, five times a day, six times a day, or more than six times a day. Administration can be about once a month, once every two weeks, once a week, or every other day. In another embodiment, the compounds of the invention and another agent are administered together about once a day to about six times a day. In another embodiment, the administration of the compounds of the invention and the agent lasts less than about 7 days. In yet another embodiment, the administration lasts more than about 6 days, 10 days, 14 days, 28 days, two months, six months, or one year. In some cases, continuous administration is achieved and the continuous administration lasts for the duration required.

[0326] The administration of the compounds of the invention can last for the duration required. In some embodiments, the administration of the compounds of the invention lasts more than 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, or 28 days. In some embodiments, the administration of the compounds of the invention lasts less than 28 days, 14 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day. In some embodiments, the compounds of the invention are administered for a long term, for example to treat chronic effects.

[0327] An effective amount of the compounds of the invention can be administered in a single dose or multiple doses by any recognized mode of administration having a similar utility (including rectal, buccal, intranasal, and transdermal routes), by intra - arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhalant.

[0328] The compositions of the present invention can also be delivered by an impregnation or coating device (e.g., a stent) or an intravascular cylindrical polymer. Such administration methods can, for example, help prevent or improve restenosis after surgery such as balloon angioplasty. Without being bound by theory, the compounds of the present invention can slow down or inhibit the restenosis - contributing migration and proliferation of smooth muscle cells in the arterial wall. The compounds of the present invention can be administered, for example, by local delivery from the struts of a stent, a stent - graft, the cover or sheath of a graft or a stent. In some embodiments, the compounds of the present invention are mixed with a matrix. Such a matrix can be a polymeric matrix and can be used to bind the compound to the stent. Polymeric matrices suitable for this use include, for example, lactone - based polyesters or copolyesters such as polylactide, polycaprolactone - glycolide, polyorthoesters, polyanhydrides, polyamino acids, polysaccharides, polyphosphazenes, poly(ether - ester) copolymers (e.g., PEO - PLLA), polydimethylsiloxane, poly(ethylene - vinyl acetate), acrylate polymers or copolymers (e.g., polyhydroxyethyl methacrylate, polyvinylpyrrolidone), fluorinated polymers (such as polytetrafluoroethylene and cellulose esters). Suitable matrices can be non - degradable or can degrade over time to release one or more compounds. The compounds of the present invention can be applied to the surface of a stent by various methods such as dip - coating / spin - coating, spraying, dipping and / or brushing. The compound can be applied in a solvent and the solvent can be allowed to evaporate to form a layer of the compound on the stent. Alternatively, the compound can be located in the body of a stent or a graft, such as in microchannels or micropores. When implanted, the compound diffuses out from the body of the stent to contact the arterial wall. Such stents can be prepared by immersing a stent manufactured to contain such micropores or microchannels into a solution of the compound of the present invention in a suitable solvent and then allowing the solvent to evaporate. Excess drug on the surface of the stent can be removed by an additional brief solvent wash. In still other embodiments, the compounds of the present invention can be covalently linked to a stent or a graft. Covalent linkers can be used that degrade in vivo to release the compounds of the present invention. Any bio - labile linkages such as ester, amide or anhydride linkages can be used for such purposes. Additionally, the compounds of the present invention can be administered intravascularly from a balloon used during angioplasty. Extravascular administration of the compound can also be carried out by pericardial or epicardial application of the formulations of the present invention to reduce restenosis.

[0329] For example, various stent devices that can be used as described are disclosed in the following references, all of which are hereby incorporated by reference: U.S. Patent No. 5,451,233; U.S. Patent No. 5,040,548; U.S. Patent No. 5,061,273; U.S. Patent No. 5,496,346; U.S. Patent No. 5,292,331; U.S. Patent No. 5,674,278; U.S. Patent No. 3,657,744; U.S. Patent No. 4,739,762; U.S. Patent No. 5,195,984; U.S. Patent No. 5,292,331; U.S. Patent No. 5,674,278; U.S. Patent No. 5,879,382; U.S. Patent No. 6,344,053.

[0330] The compounds of the invention can be administered in doses. It is known in the art that, due to variability in compound pharmacokinetics among subjects, individualization of the dosing regimen is necessary for optimal therapy. The dosing of the compounds of the invention can be found by routine experimentation in accordance with this disclosure.

[0331] When the compounds of the invention are administered in the form of a composition comprising one or more pharmaceutical agents and the half-life of the pharmaceutical agent is shorter than the half-life of the compounds of the invention, the unit dosage forms of the pharmaceutical agent and the compounds of the invention can be adjusted accordingly.

[0332] The pharmaceutical compositions of the invention can be, for example, in a form suitable for oral administration in the form of tablets, capsules, pills, powders, sustained-release formulations, solutions, suspensions, suitable for parenteral injection in the form of sterile solutions, suspensions or emulsions, suitable for topical application in the form of ointments or creams or suitable for rectal administration in the form of suppositories. The pharmaceutical compositions can be in unit dosage forms suitable for administering an exact dose in a single administration. The pharmaceutical compositions will comprise a conventional pharmaceutical carrier or excipient and a compound according to the invention as the active ingredient. In addition, the pharmaceutical compositions can include other medicinal agents, carriers, adjuvants, etc.

[0333] Exemplary parenteral administration forms include solutions or suspensions of the active compound in a sterile aqueous solution, such as an aqueous solution of propylene glycol or an aqueous solution of glucose. If desired, such dosage forms can be buffered appropriately.

[0334] Methods of Use

[0335] The method generally involves administering a therapeutically effective amount of a compound of the present invention to a subject. The therapeutically effective amount of the compound combination of the present invention may vary depending on the intended application (in vitro or in vivo) or the subject being treated and the condition (e.g., the weight and age of the subject, the severity of the condition, the mode of administration, etc.) that can be readily determined by a person of ordinary skill in the art. The term also applies to the dose that will induce a specific response in the target cell (e.g., a decrease in the proliferation of the target protein or a downregulation of its activity). The specific dose will vary depending on the specific compound selected, the dosing regimen followed, whether it is administered in combination with other compounds, the timing of administration, the tissue administered to, and the physical delivery system by which it is carried.

[0336] In certain embodiments, the present invention provides a pharmaceutical composition comprising a bispecific compound or a pharmaceutically acceptable salt thereof.

[0337] In certain embodiments, the present invention provides a pharmaceutical composition comprising a bispecific compound for degrading a target protein in a cell.

[0338] In certain embodiments, a method of degrading a target protein comprises administering a therapeutically effective amount of a bispecific compound or a pharmaceutically acceptable salt to a cell, wherein the compound effectively degrades the target protein.

[0339] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of bispecific formula, the pharmaceutical composition being for treating or preventing a disease or disorder in which SMARCA2 and / or SMARCA4 plays a role.

[0340] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of bispecific formula, the pharmaceutical composition being for treating or preventing a disease or disorder in which the SWI / SNF mutation plays a role.

[0341] In certain embodiments, the target protein is SMARCA2, SMARCA4, and / or PB1.

[0342] In certain embodiments, the target protein complex is SWI / SNF in a cell.

[0343] In certain embodiments, diseases or disorders that are dependent on SMARCA2 or SMARCA4 include cancer.

[0344] In certain embodiments, diseases or disorders that are dependent on the SWI / SNF complex include cancer.

[0345] Exemplary cancers that can be treated by the compounds of the present invention alone or in combination with at least one additional anti-cancer agent include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and renal cell carcinoma, bladder cancer, bowel cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer; leukemia; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative disorders; sarcomas, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, rhabdomyosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineocytoma, meningioma, meningeal sarcoma, neurofibroma and schwannoma; bowel 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.

[0346] In certain embodiments, cancers that can be treated using the compounds according to the present disclosure include, for example, T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-B ALL, pre-B lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML.

[0347] In certain other embodiments, the cancer is a SMARCA2 and / or SMARAC4-dependent cancer.

[0348] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of a bispecific format, the pharmaceutical composition for use in a disease or disorder that is dependent on SMARCA2 and / or SMARCA4, the disease or disorder being cancer.

[0349] The compounds of the present disclosure and pharmaceutical compositions comprising the compounds can be administered alone or in combination with medical therapies to treat any of the diseases described. Medical therapies include, for example, surgery and radiotherapy (e.g., γ-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, systemic radioisotopes).

[0350] In other aspects, the compounds of the present disclosure and pharmaceutical compositions comprising the compounds can be administered alone or in combination with one or more other agents to treat any of the diseases described.

[0351] In other methods, the compounds of the present disclosure and pharmaceutical compositions comprising the compounds can be administered in combination with an agonist of a nuclear receptor agent.

[0352] In other methods, the compounds of the present disclosure and pharmaceutical compositions comprising the compounds can be administered in combination with an antagonist of a nuclear receptor agent.

[0353] In other methods, the compounds of the present disclosure and pharmaceutical compositions comprising the compounds can be administered in combination with an anti - proliferative agent.

[0354] Combination Therapies

[0355] For the treatment of cancer and other proliferative diseases, the compounds of the present invention can be used in combination with chemotherapeutic agents, agonists or antagonists of nuclear receptors, or other anti-proliferative agents. The compounds of the present invention can also be used in combination with medical therapies such as surgery or radiation therapy, such as γ-radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes. Examples of suitable chemotherapeutic agents include any of the following: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, all-trans retinoic acid, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bendamustine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citratecitrate), filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alpha 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C (mitomycinC), Mitotane, Mitoxantrone, Nandrolone, Phenpropionate, Nelarabine, Nofetumomab, Oxaliplatin, Paclitaxel, Pamidronate, Panobinostat, Panitumumab, Pegaspargase, Pegfilgrastim, Pemetrexed disodium, Pentostatin, Pipobroman, Plicamycin, Procarbazine, Quinacrine, Rasburicase, Rituximab, Ruxolitinib, Sorafenib, Streptozocin, Sunitinib, Sunitinib maleate, Tamoxifen, Temozolomide, Teniposide, Testolactone, Thalidomide, Thioguanine, Thiotepa, Topotecan, Toremifene, Tositumomab, Trastuzumab, Tretinoin, Uracil mustard, Valrubicin, Vinblastine, Vincristine, Vinorelbine, Vorinstat and Zoledronate.

[0356] 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 acetyltransferase 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.

[0357] For the treatment of cancer and other proliferative diseases, the compounds of the present invention can be used in combination with targeted therapies, which include JAK kinase inhibitors (such as ruxolitinib), PI3 kinase inhibitors (including PI3K-δ selective and broad-spectrum PI3K inhibitors), MEK inhibitors, cyclin-dependent kinase inhibitors (including CDK4 / 6 inhibitors and CDK9 inhibitors), BRAF inhibitors, mTOR inhibitors, proteasome inhibitors (such as bortezomib, Carfilzomib), HDAC inhibitors (such as panobinostat, vorinostat), DNA methyltransferase inhibitors, dexamethasone, bromodomain and extra-terminal family member (BET) inhibitors, BTK inhibitors (such as ibrutinib, acalabrutinib), BCL2 inhibitors (such as venetoclax), dual BCL2 family inhibitors (such as BCL2 / BCLxL), PARP inhibitors, FLT3 inhibitors, or LSD1 inhibitors.

[0358] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1, such as an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), or PDR001. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-L1, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is atezolizumab, durvalumab, or BMS-935559. In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab.

[0359] 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).

[0360] The compounds of the present invention can be prepared using a variety of preparation reactions known in the literature. The following schemes provide general guidance on the preparation of the compounds of the present invention. Those skilled in the art will understand that the preparations shown in the schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the present invention. Example synthetic methods for preparing the compounds of the present invention are provided in the following schemes.

[0361] The following examples are provided to illustrate some of the concepts described within the present disclosure. While the examples are considered to provide embodiments, they should not be considered to limit the more general embodiments described herein.

[0362] Examples

[0363] General Synthetic Procedures

[0364] The compounds described herein can be prepared according to the following synthetic schemes and general synthetic procedures.

[0365] Scheme 1

[0366]

[0367] Intermediate 1-6, where X1 = CO and X2 = CH2, can be synthesized according to the route described in Scheme 1. The S between fluorophenyl 1-1 and amine 1-2 N Ar By using an appropriate base (e.g., DIPEA, K2CO3, etc.) and heating in a suitable solvent (DMF, DMSO, THF, etc.), compound 1-3 can be obtained. Under appropriate conditions (e.g., Raney Nickel), the reduction of the nitrile in 1-3 can be achieved to obtain 1-4. The reductive amination and cyclization of 1-4 with 1-5 (e.g., DIPEA, followed by AcOH and sodium triacetoxyborohydride) provide Intermediate 1-6.

[0368] Scheme 2

[0369]

[0370] Intermediate 1-6, where X1 = CH2 and X2 = CO, can be synthesized according to the route described in Scheme 2. The S between fluorophenyl 2-1 and amine 1-2 N Ar By using an appropriate base (e.g., DIPEA, K2CO3, etc.) and heating in a suitable solvent (DMF, DMSO, THF, etc.), compound 2-2 can be obtained. Under appropriate conditions (e.g., Raney Nickel), the reduction of the nitrile in 2-2 can be achieved to obtain 2-3. The reductive amination and cyclization of 2-3 with 1-5 (e.g., DIPEA, followed by AcOH and sodium triacetoxyborohydride) provide Intermediate 1-6.

[0371] Scheme 3

[0372]

[0373] Intermediate 1-6, where X1 and X2 = CO, can be synthesized according to the route described in Scheme 3. The S between fluorophenyl 3-1 and amine 1-2 N Ar By using an appropriate base (e.g., DIPEA, K2CO3, etc.) and heating in a suitable solvent (DMF, DMSO, THF, etc.), compound 1-6 can be obtained.

[0374] Scheme 4

[0375]

[0376] Intermediate 1-6, where X1 = CO and X2 = CH2, can be synthesized according to the route described in Scheme 4. Halogenation of 4-1 (e.g., NBS and peroxides, etc.) in a suitable solvent (such as DCE, etc.) can give compound 4-2. 4-2 can be converted to 4-3 using an appropriate oxidant (e.g., aqueous AgNO3 and IPA, etc.). 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, the halide 4-3 is coupled with A2 (where M = B(OH)2, B(OR)2 or SnR3) to give intermediate 1-4. Reductive amination and cyclization of 1-4 with 1-5 (e.g., DIPEA, followed by AcOH and sodium triacetoxyborohydride) gives compound 1-6.

[0377] Scheme 5

[0378]

[0379] The enantiomerically pure intermediate 5-3, where 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. Then 5-2 is cyclized using an appropriate base (such as KOtBu) to provide intermediate 5-3.

[0380] Scheme 6

[0381]

[0382] The tricyclic intermediate 6-11, where R4 = H, can be synthesized according to the route described in Scheme 6. The -NH and -OH groups of the commercially available starting material 6-1 are protected with appropriate protecting groups (e.g., Boc, SEM, Bn, TBDMS, etc.), and then esterified to give the ester 6-2. The conversion of 6-2 to 6-3 can be achieved using a reducing agent (e.g., LiAlH4, DIBAL-H, etc.). The hydroxyl group in 6-3 is substituted to give the azide 6-4 by conversion to a leaving group under appropriate conditions (e.g., TsCl / Et3N, MsCl / Et3N, etc.) followed by substitution (e.g., NaN3). Alternatively, compound 6-3 can be converted to the azide 6-4 under Mitsunobu conditions ((PhO)2PON3, THF containing DEAD). Deprotection of 6-4 (e.g., TFA or HCl for Boc deprotection) gives the amine 6-5. In the presence of a base such as DIPEA, the S N AR reaction between the amine 6-5 and the pyridazine 6-6 gives the intermediate 6-7. Reduction of the azide group in compound 6-7 by Staudinger reduction or hydrogenation, followed by intramolecular cyclization provides compound 6-8. Protection of the -NH group and deprotection of -OPG then gives compound 6-9. The halide 6-9 is coupled with the phenol 6-10 (where M = B(OH)2, B(OR)2 or SnR3) in a suitable solvent (such as dioxane or DMF) in the presence of a palladium catalyst (e.g., tetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) and a base (e.g., CsF, Na2CO3 or Cs2CO3), with or without water as a co-solvent, under standard cross-coupling conditions to give the intermediate 6-11.

[0383] Scheme 7

[0384]

[0385] The compound of formula (I) can be synthesized according to the route described in Scheme 7. The Mitsunobu reaction of the alcohol in compound 6-9 with A1, where Z = SH, OH or NHR3, gives compound 7-1. The cross-coupling of the halide 7-1 with the phenol 6-10, where the phenol is optionally protected and then deprotected, gives the intermediate 7-2. Reaction of 7-2 with 1-6 (or 5-3) by reductive amination or substitution gives the compound of formula (I).

[0386] Scheme 8

[0387]

[0388] The compound of formula (I) can be prepared according to the route described in Scheme 8. Mesylation of the alcohol in Compounds 6-11, followed by substitution with A1 and deprotection, gives Compound 7-2. Subsequently, reductive amination of 7-2 with 1-6 (or 5-3) gives the compound of formula (I).

[0389] Scheme 9

[0390]

[0391] The compound of formula (I) can be prepared according to the route described in Scheme 9. Mesylation of the alcohol in Compound 6-9, followed by substitution with A1, gives Compound 7-1. Cross-coupling of the halide 7-1 with phenol 9-1, followed by deprotection, gives the intermediate 7-2. Reacting the intermediate 7-2 with 1-6 (or 5-3) by reductive amination or substitution gives the compound of formula (I).

[0392] Scheme 10

[0393]

[0394] The compound of formula (I) can be prepared according to the route described in Scheme 10. Mesylation of the alcohol in Compound 6-9, followed by substitution with cyanide (e.g., NaCN, KCN), gives nitrile 10-1. Cross-coupling of 10-1 with phenol 9-1, followed by deprotection, gives the intermediate 10-2. Hydrolysis of the nitrile in 10-2, followed by amide coupling (e.g., HATU, DMF containing DIPEA) provides Compound 10-4 (where L1 = CO). Reacting 10-4 with 1-6 (or 5-3) by reductive amination gives the compound of formula (I).

[0395] Scheme 11

[0396]

[0397] The compound of formula (I) can be synthesized according to the route described in Scheme 11. Mesylation of the alcohol in Compound 6-9, followed by substitution with NH2R3, gives amine 11-1. 11-1 reacts with A1 (where X = halogen) and S N Ar to give Compound 11-2. Cross-coupling of 11-2 with phenol 9-1 then provides the intermediate 11-3. Reacting 11-3 with 1-6 (or 5-3) by reductive amination gives the compound of formula (I).

[0398] Scheme 12

[0399]

[0400] The compound of formula (I) where R4 ≠ H can be synthesized according to the route outlined in Scheme 12. Esterification of the commercially available acid 12-1, followed by alkylation, provides compound 12-3, which can be hydrolyzed to obtain 12-4. Formation of an amide with 12-5 yields intermediate 12-6, which can be subjected to deprotection and cyclization to give the tricyclic 12-7. Reduction of the amide gives the amine 6-8 (where R4 ≠ R), which can subsequently be converted to the compound of formula (I) by the steps outlined in Scheme 6-11.

[0401] Intermediate 1: (6aR,8S)-2-chloro-8-hydroxy-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-5(6H)-carboxylic acid tert-butyl ester

[0402]

[0403] Step 1: (2R,4S)-1-(tert-butoxycarbonyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylic acid

[0404]

[0405] 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 h, 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). An aqueous solution of lithium hydroxide (176 mg) in water (9 mL) was added and the mixture was stirred at room temperature for three hours. The mixture was poured into water, acidified to pH ~2 with 1 N HCl, extracted with 20% MTBE / hexane (v / v) (3 x 50 mL) and washed with brine (50 mL). The organic fraction was dried over MgSO4, filtered and concentrated under reduced pressure to give (2R,4S)-1-(tert-butoxycarbonyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylic acid (assumed quantitative yield, 4.3 mmol). C 11 H 24 NO3Si (M+2H-Boc) + LCMS calculated value for m / z: 246.2; experimental value: 246.1.

[0406] Step 2: (2R,4S)-4-((tert-Butyldimethylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0407]

[0408] At 0 °C, BH3·SMe2 (0.82 mL, 8.6 mmol) was added dropwise to 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). The solution was warmed to room temperature and stirred for 24 h. The reaction mixture was quenched with saturated aqueous NH4Cl, extracted with EtOAc (2 x 25 mL), washed with brine (25 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford (2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (assumed quantitative yield, 4.3 mmol). C 12 H 26 NO4Si (M+2H-tBu) + LCMS calculated value for m / z: 276.2; experimental value: 276.0.

[0409] Step 3: (2R,4S)-4-((tert-Butyldimethylsilyl)oxy)-2-((tosyloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0410]

[0411] At 0 °C, pyridine (2.6 mL) was added to a solution of (2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.4 g, 4.3 mmol) and 4-methylbenzenesulfonyl chloride (1.0 g, 5.4 mmol) in DCM (8.6 mL). The reaction was warmed to room temperature and stirred for 23 h. The reaction mixture was diluted with DCM and washed with water (2 x 50 mL), 10 wt% aqueous citric acid (2 x 50 mL), brine (50 mL), and dried over MgSO4. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (0 - 100% EtOAc / hexanes) on a silica gel column to afford (2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-((tosyloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester as a clear oil (1.6 g, 3.3 mmol, 76% yield). C 18H 32 NO4SSi (M+H-Boc) + LCMS calculated value for m / z: 386.2; experimental value: 386.1.

[0412] Step 4: (2R,4S)-2-(azidomethyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[0413]

[0414] To a solution of (2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-((tosyloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (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 h. The reaction mixture was cooled to room temperature, diluted with MTBE, and then washed with water (4 x 50 mL) and brine (50 mL). The organic layer was filtered and concentrated under reduced pressure to afford (2R,4S)-2-(azidomethyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester as a clear oil (343 mg, 94% yield), which was used without further purification. C 4干燥， H 12 H 25 N4O3Si (M+H-tBu) + LCMS calculated value for m / z: 301.2; experimental value: 301.0.

[0415] Step 5: (2R,4S)-2-(azidomethyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine

[0416]

[0417] 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 h and basified to pH ~12 with 2 N aqueous NaOH. The reaction mixture was extracted with DCM (3 x 25 mL), washed with brine (25 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford (2R,4S)-2-(azidomethyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine as a clear oil (165 mg, 67% yield), which was used without further purification. C 11 H 25 N4OSi (M+H) + LCMS calculated for m / z: 257.2; found: 257.1.

[0418] Step 6: 4-((2R,4S)-2-(Azidomethyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-3,6-dichloropyridazine

[0419]

[0420] 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 mixture was stirred at 80 °C for 20 h, then poured into water and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with water (4 x 50 mL), then with brine (50 mL), then dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to afford 4-((2R,4S)-2-(azidomethyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-3,6-dichloropyridazine (144 mg, 56% yield), which was used without further purification. C 15 H 25 Cl2N6OSi (M+H) + LCMS calculated for m / z: 403.1 / 405.1; found: 403.0 / 405.0. 11H NMR (400 MHz, DMSO) δ 7.41 (s, 1H), 4.59 (tt, J = 7.6, 3.7 Hz, 1H), 4.56 – 4.51 (m, 1H), 3.93 (dd, J = 11.3, 3.4 Hz, 1H), 3.69 (dd, J = 13.2, 4.5 Hz, 1H), 3.39 – 3.28 (m, 5H), 2.08 – 1.95 (m, 2H), 0.77 (s, 9H), 0.06 (s, 3H).

[0421] 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

[0422]

[0423] 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 minutes. 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 hours. The mixture was cooled to room temperature and then extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give (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 of crude product, 0.36 mmol, assumed quantitative yield), which was used without further purification. C 15 H 26 ClN4OSi (M+H) + LCMS calculated for m / z: 341.2 / 343.2; found: 341.0 / 342.9.

[0424] 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)-carboxylic acid tert-butyl ester

[0425]

[0426] To a mixture of (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 h, then charged with additional di-tert-butyl dicarbonate (156 mg, 0.71 mmol) and 4-(dimethylaminopyridine) (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-butyldimethylsilyl)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). C 20 H 34 ClN4O3Si (M+H) + LCMS calculated for m / z: 441.2 / 443.2; found: 441.1 / 443.0.

[0427] Step 9: 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

[0428] At 0 °C, tetrabutylammonium fluoride (1 M in THF, 3.1 mL, 3.1 mmol) was added 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). The mixture was stirred at 0 °C for 5 minutes and then allowed to stir at room temperature for 19 hours. NH4Cl (saturated aqueous solution) was added to the reaction and the mixture was extracted with DCM (3 x 25 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% EtOAc / hexane) 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 as a yellow-orange solid (251 mg, 0.77 mmol, 62% yield). C 14 H 20 ClN4O3 (M+H) + LCMS calculated for m / z: 327.1 / 329.1; found: 327.0 / 328.9.

[0429] Intermediate 2: 3-(1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

[0430]

[0431] Step 1: tert-butyl 4-(4-cyano-3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[0432]

[0433] To a solution of methyl 2-cyano-5-fluorobenzoate (5.00 g, 27.9 mmol) and tert-butyl piperazine-1-carboxylate (15.6 g, 83.7 mmol) in NMP (20.0 mL) was added N,N-diisopropylethylamine (7.29 mL, 41.9 mmol). The solution was heated at 120 °C for 4 hours and then cooled to -20 °C overnight. The solid product observed was filtered and washed with heptane to afford tert-butyl 4-(4-cyano-3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate as a yellow solid. C 13 H 16 N3O2(M-Boc+2H) +LCMS calculated value of m / z: 246.1; experimental value: 245.9

[0434] Step 2: tert-Butyl 4-(4-formyl-3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[0435]

[0436] 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; phosphonate; hydrate (17.2 g, 162 mmol) and water (10.0 mL), followed by addition of Raney nickel (9.52 g, 162.14 mmol). The reaction mixture was heated to 75 °C for 7 hours and monitored by HPLC, and only about 50% conversion was seen. An additional 1.0 equivalent of Raney nickel was added and heated overnight at 75 °C. HPLC monitoring showed about 94% conversion. The reaction mixture was cooled and diluted with MeOH, filtered through diatomaceous earth, 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 obtain the crude product, which was purified by FCC (0% to 60% ethyl acetate / heptane) to obtain tert-butyl 4-(4-formyl-3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (13.5 g, 47.8%). 1 1H NMR (300 MHz, DMSO) δ 10.02 (s, 1H), 7.83 07.73 (m, 1H), 7.17 (dd, J = 12.7, 2.5 Hz, 2H), 3.86 (s, 3H), 3.44 (s, 8H), 3.32 (s, 2H), 1.42 (s, 9H).

[0437] Step 3: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazine-1-carboxylate

[0438]

[0439] 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 mixture was stirred at room temperature for 1 h and acetic acid (5.25 mL, 91.9 mmol) was added to this solution. The reaction mixture was stirred for an additional hour and sodium triacetoxyborohydride (5.84 g, 27.6 mmol) was added. The reaction mixture was stirred overnight to check for complete conversion, monitored by HPLC. The reaction was stopped and diluted with DCM (50.0 mL) and quenched dropwise with saturated NaHCO3 solution until the pH was maintained at 8 - 9. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude material. Purification by FCC (0% to 80% EA / heptane) gave tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazine-1-carboxylate (3.00 g, 76.3%). C 22 H 29 N4O5 (M+H) + LCMS calculated for m / z: 429.2; found: 428.9.

[0440] Step 4: 3-(1-Oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

[0441] At 0 °C, 2,2,2-trifluoroacetic acid; TFA (20.0 mL, 261.36 mmol) was added dropwise 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 (80.0 mL). The reaction mixture was stirred at room temperature for 3 h to observe complete conversion by HPLC. The DCM and TFA were concentrated and then further diluted with 10 mL of CHCl3:IPA (3:1). At 0 °C, 10% Na2CO3 was added dropwise to this solution to observe the formation of a precipitate with pH around 8 - 9. The solid was filtered and dried to afford the desired product 3-(1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (2.60 g, 89.3%). C 17 H 21 N4O3 (M+2H-Boc) + LCMS calculated for m / z: 329.2; found: 329.1

[0442] Intermediate 3: 1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-4-carbaldehyde

[0443]

[0444] Step 1: Methyl 5-amino-4-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate

[0445]

[0446] Using a procedure similar to that described for Intermediate 2, Steps 1 - 3, prepare the title compound using the appropriate starting materials.

[0447] Step 2: 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0448]

[0449] At -78 °C, a 1.0 M solution of potassium tert-butoxide (8.30 mL, 8.30 mmol) in THF 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) and the reaction mixture was stirred for 3 h. The reaction mixture was warmed to 0 °C and the pH was carefully adjusted to approximately 3 using 1 N aqueous HCl. A saturated aqueous solution of NaHCO3 was carefully added dropwise to this solution to adjust the pH to approximately 6. DCM was added and the phases were separated. The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was triturated with DCM (5.00 mL), then with MTBE (20.0 mL), and thereafter a white precipitate was deposited. The solid was filtered and dried by vacuum filtration to afford 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.89 g, 68% yield). 11H NMR (300 MHz, DMSO) δ 10.97 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.25 (dd, J = 8.5, 2.3 Hz, 1H), 7.14 (d, J = 2.2 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.33 (d, J = 16.8 Hz, 1H), 4.19 (d, J = 16.7 Hz, 1H), 4.08 (d, J = 6.6 Hz, 1H), 3.77 (d, J = 12.3 Hz, 2H), 3.27 (s, 6H), 2.98 – 2.82 (m, 1H), 2.65 (dd, J = 29.4, 15.4 Hz, 3H), 2.38 (qd, J = 13.3, 4.4 Hz, 1H), 2.04 – 1.92 (m, 1H), 1.72 (d, J = 10.8 Hz, 3H), 1.34 (dt, J = 21.6, 10.9 Hz, 2H).

[0450] Step 3: 1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-4-carbaldehyde

[0451] 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 mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure to afford 1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-4-carbaldehyde (440 mg, quantitative yield) as the TFA salt. C 19 H 22 N3O4 (M+H) + LCMS calculated for m / z: 356.2; found: 356.2.

[0452] Intermediate 4: Methyl 4-methylbenzenesulfonate (1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-4-yl)methyl ester

[0453]

[0454] Step 1: Methyl 2-cyano-5-(4-(hydroxymethyl)piperidin-1-yl)benzoate

[0455]

[0456] 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-diisopropylethylamine (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 solution (50 mL × 2). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (eluting with a gradient of 0 - 100% EtOAc / hexane) to afford methyl 2-cyano-5-(4-(hydroxymethyl)piperidin-1-yl)benzoate as a yellow oil (3.02 g, 98% yield). C 15 H 18 N2O3 [M+H] + LCMS calculated for m / z: 275.1; found: 275.1.

[0457] Step 2: Methyl 2-formyl-5-(4-(hydroxymethyl)piperidin-1-yl)benzoate

[0458]

[0459] 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 h. 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 flash column chromatography on silica gel (eluting with a gradient of 0 - 100% EtOAc / hexane) to give methyl 2-formyl-5-(4-(hydroxymethyl)piperidin-1-yl)benzoate as a yellow oil (2.31 g, 76.0%). C 15 H 20NO4 [M+H] + LCMS calculated value of m / z: 278.1; experimental value: 278.1.

[0460] Step 3: 3-(6-(4-(Hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0461]

[0462] 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 h. 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 slowly warmed to room temperature and stirred for an additional 3 h. The reaction mixture was diluted with water (10 mL) and the solution was basified with saturated aqueous NaHCO3 until no further evolution of gas was observed. The basified product mixture was filtered and the solid was washed with water (10 mL × 2). The solid was collected and dried under vacuum to afford 3-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione as an off-white solid (1.95 g, 63%). C 19 H 23 N3O4 [M+H] + LCMS calculated value of m / z: 358.2; experimental value: 358.1.

[0463] Step 4: Methyl 4-methylbenzenesulfonate (1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-4-yl)

[0464] p-Toluenesulfonyl 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 mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM, and the organic layer was washed with water, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (eluting with a gradient of 0 - 100% EtOAc / DCM) to afford (1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-4-yl)methyl 4-methylbenzenesulfonate as an off-white solid (43.7 mg, 31%). C 19 H 23 N3O4 [M+H] + LCMS calculated for m / z: 512.4; found: 511.7.

[0465] Intermediate 5: 3-(1-Oxo-6-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0466]

[0467] Step 1: Methyl 5-bromo-2-(dibromomethyl)benzoate

[0468]

[0469] A suspension of methyl 5-bromobenzoate (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% Na2S2O3 solution (100 mL), saturated NaHCO3 solution (100 mL), water (100 mL) and brine (100 mL), then dried over Na2SO4, filtered and concentrated. The residue was dried under high vacuum to afford the desired product, methyl 5-bromo-2-(dibromomethyl)benzoate, as a pale yellow solid (9.875 g, 96.1%). 1 1H NMR (300 MHz, CDCl3) δ 8.04 (dd, J = 5.4, 3.1 Hz, 2H), 7.97 (s,1H), 7.74 (dd, J = 8.6, 2.1 Hz, 1H), 3.96 (s, 3H).

[0470] Step 2: Methyl 5-bromo-2-formylbenzoate

[0471]

[0472] Dissolve silver nitrate (6.57 g, 38.7 mmol) in water (60.0 mL). Add this solution 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. When HPLC indicates the disappearance of the starting material, stir the resulting mixture at ambient temperature in the dark for 4 h. Filter off the precipitated silver salt and wash with small portions of IPA. Evaporate the IPA under reduced pressure and extract the remaining aqueous phase with EtOAc (50.0 mL × 3). Wash the combined organic phases with water (50.0 mL), brine (50.0 mL), dry over Na2SO4, filter and concentrate under reduced pressure. Dry the residue under high vacuum to afford the desired product, methyl 5-bromo-2-formylbenzoate, as a white solid (3.26 g, 13.4, 86.8%). C9H8BrO3 (M+H) + LCMS calculated for m / z: 242.9; found: 242.8. 1 1H NMR (300 MHz, CDCl3) δ 10.58 (s, 1H), 8.13 (d, J = 1.5 Hz, 1H), 7.85–7.76 (m, 2H), 3.99 (s, 3H).

[0473] Step 3: tert-Butyl 4-(4-formyl-3-methoxycarbonylphenyl)-3,6-dihydro-2H-pyridine-1-carboxylate

[0474]

[0475] When HPLC indicated 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)Cl2 (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 N2 atmosphere. The reaction mixture 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 Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (0 - 25% EtOAc / heptane) to afford 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. R f = 0.4 (25% EtOAc / heptane). 1 1H NMR (300 MHz, CDCl3) δ 10.57 (s, 1H), 7.93 (t, J = 4.8 Hz, 2H), 7.63 (dd, J = 8.1, 1.5 Hz, 1H), 6.25 (s, 1H), 4.12 (d, J = 2.8 Hz, 2H), 3.98 (s, 3H), 3.66 (t, J = 5.7 Hz, 2H), 2.56 (d, J = 1.4 Hz, 2H), 1.49 (s, 9H).

[0476] Step 4: tert-Butyl 4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate

[0477]

[0478] 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. Then AcOH (0.31 mL, 5.39 mmol) was added and the mixture was stirred for 1 hour. NaBH(OAc)3 (571 mg, 2.69 mmol) was added in portions, and the reaction solution was stirred at ambient temperature for 18 hours. The reaction solution was diluted with DCM (150 mL), washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (0 - 5% MeOH / 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. R f = 0.3 (5% MeOH / DCM). C 23 H 28 N3O5 (M+H) + LCMS calculated for m / z: 426.2; found: 426.0. 1 H NMR (300 MHz, DMSO) δ 10.99 (s, 1H), 7.77 – 7.69 (m, 2H), 7.58 (d, J = 8.5 Hz, 1H), 6.28 (s, 1H), 5.13 (dd, J = 13.2, 5.1 Hz, 1H), 4.39 (dd, J = 41.6, 17.4 Hz, 2H), 4.02 (s, 2H), 3.57 (dd, J = 10.6, 5.1 Hz, 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).

[0479] Step 5: tert-Butyl 4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]piperidine-1-carboxylate

[0480]

[0481] tert-Butyl 4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]piperidine-1-carboxylate (290 mg, 0.680 mmol) in MeOH (5.00 mL) and THF (5.00 mL) was hydrogenated at 30 psi with 10% Pd / C for 2 h. The solid material was filtered off and washed with MeOH in small portions. The filtrate was concentrated and the residue was purified by flash column chromatography on silica gel (0 - 4% MeOH / DCM) to afford tert-Butyl 4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]piperidine-1-carboxylate as a white solid (265 mg, 90.9%). R f = 0.25 (5% MeOH / DCM). C 23 H 30 N3O5 (M+H) + LCMS calculated for m / z: 428.2; found: 427.9. 1 1H NMR (300 MHz, DMSO) δ 10.99 (s, 1H), 7.55 (d, J = 11.3 Hz, 3H), 5.11 (dd, J = 13.2, 5.0 Hz, 1H), 4.35 (dd, J = 41.1, 17.1 Hz, 2H), 4.09 (d, J = 12.2 Hz, 2H), 2.98 – 2.79 (m, 3H), 2.70 – 2.55 (m, 2H), 2.39 (ddd, J = 26.2, 13.3, 4.3 Hz, 1H), 1.98 (dd, J = 11.3, 4.6 Hz, 1H), 1.83 – 1.73 (m, 2H), 1.65 – 1.49 (m, 2H), 1.40 (d, J = 11.4 Hz, 9H).

[0482] Step 6: 3-(1-Oxo-6-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0483] The title compound was prepared using a procedure similar to that described in Intermediate 2, Step 4, using tert-Butyl 4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]piperidine-1-carboxylate instead of tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazine-1-carboxylate, C 18 H 22 N3O3 [M+H] +LCMS calculated value of m / z: 328.2; experimental value: 328.1.

[0484] Intermediate 6: (S)-3-(1-oxo-6-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0485]

[0486] 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

[0487]

[0488] 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)-NH2 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 minutes. Then AcOH (2.86 mL, 50.0 mol) was added and the mixture was stirred for 1 hour. NaBH(OAc)3 (5.30 g, 25.0 mmol) was added in portions, and the reaction solution was stirred at ambient temperature for 18 hours. The reaction solution was diluted with DCM (150 mL), washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (0 - 5% MeOH / DCM) to afford the desired product (S)-tert-butyl 4-(2-(1-amino-5-methoxy-1,5-dioxopentan-2-yl)-3-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate as a white solid (3.01 g, 78.9%). R f = 0.3 (5% MeOH / DCM). C 24 H 32 N3O6 (M+H) + LCMS calculated value of m / z: 458.2; experimental value: 458.1. 11H NMR (300 MHz, DMSO) δ 7.75 – 7.67 (m, 2H), 7.57 (d, J = 8.3 Hz, 2H), 7.20 (s, 1H), 6.26 (s, 1H), 4.75 (dd, J = 10.2, 4.6 Hz, 1H), 4.52 (dd, J = 45.0, 17.7 Hz, 2H), 4.02 (d, J = 7.1 Hz, 2H), 3.56 (t, J = 5.5 Hz, 2H), 3.50 (s, 3H), 2.58 – 2.50 (m, 2H), 2.29 – 1.96 (m, 4H), 1.43 (s, 9H).

[0489] Step 2: tert-Butyl (S)-4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0490]

[0491] At -78 °C, t-BuOK (1.0 M in THF, 2.75 mmol, 2.75 mL) was added dropwise to a solution of 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). The resulting mixture was stirred at -78 °C for 2 h. The reaction was quenched by adding 1 N HCl solution until pH 6 and extracted with DCM (50 mL × 3). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was suspended in the 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 as a white solid (718 mg, 1.69 mmol, 76.7% yield). C 19 H 20 N3O5 (M+2H- t Bu) + LCMS calculated for m / z: 370.14; found: 370.09. 11H NMR (300 MHz, DMSO) δ 10.99 (s, 1H), 7.75– 7.71 (m, 2H), 7.58 (d, J = 8.5 Hz, 1H), 6.28 (s, 1H), 5.13 (dd, J = 13.2,5.1 Hz, 1H), 4.39 (dd, J = 41.6, 17.5 Hz, 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, 3.1 Hz, 1H), 1.43 (s, 9H).

[0492] Step 3: tert-Butyl (S)-4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-1-carboxylate

[0493]

[0494] A solution of tert-butyl (S)-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 at 30 psi with 10% Pd / C for 2 h. The solid material was filtered off and washed with MeOH in portions. The filtrate was concentrated and the residue was purified by flash column chromatography on silica gel (0 - 4% MeOH / DCM) to afford tert-butyl (S)-4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-1-carboxylate (809 mg, 98.4%) as a white solid. R f = 0.25 (5% MeOH / DCM). C 19 H 22 N3O5 (M+2H-tBu) + LCMS calculated for m / z: 372.2; found: 372.0. 11H NMR (300 MHz, DMSO) δ 10.99 (s, 1H), 7.55 (d, J = 11.0 Hz, 3H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.35 (dd, J = 41.3, 17.1 Hz, 2H), 4.08 (d, J = 10.3 Hz, 2H), 2.99 – 2.74 (m, 4H), 2.59 (dd, J = 15.4, 2.2 Hz, 1H), 2.39 (qd, J = 13.1, 4.3 Hz, 1H), 2.10 – 1.92 (m, 1H), 1.79 (d, J = 12.1 Hz, 2H), 1.66 – 1.45 (m, 2H), 1.42 (s, 9H).

[0495] Step 4: (S)-3-(1-Oxo-6-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione; hydrochloride

[0496] (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 1,4-dioxane (15.0 mL) containing 4 N HCl was added at 0 °C. The reaction mixture was stirred at ambient temperature for 18 h. The white precipitate was filtered off and washed in small portions with 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.

[0497] Intermediate 7: (S)-3-(1-Oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione; hydrochloride

[0498]

[0499] Step 1: tert-Butyl 4-(4-cyano-3-methoxycarbonylphenyl)piperazine-1-carboxylate

[0500]

[0501] 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-diisopropylethylamine (0.01 mL, 0.04 mmol), and the mixture was heated to 120 °C for 4 h. HPLC monitoring after 4 h showed consumption of the starting materials. The reaction mixture was cooled to -20 °C overnight and the product was triturated. The solid was filtered and washed with heptane to afford the desired product tert-butyl 4-(4-cyano-3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (28.0 g, 72.6%). C 13 H 16 N3O2 (M+2H-Boc) + LCMS calculated for m / z: 246.17; found: 245.99. 1 H NMR (300 MHz, DMSO) δ 7.73 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 2.7 Hz, 1H), 7.22 (dd, J = 8.8, 2.7 Hz, 1H), 3.89 (s, 3H), 3.51 – 3.38 (m, 8H), 1.42 (s, 9H).

[0502] Step 2: tert-Butyl 4-(4-formyl-3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[0503]

[0504] 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 hypophosphite monohydrate (4.97 g, 46.9 mmol) and water (10.0 mL). Raney nickel (2.75 g, 46.9 mmol) was added portionwise to the stirred solution to avoid emulsion formation. The reaction mixture was heated to 75 °C for 7 h and monitored by HPLC, and only about 50% conversion was observed. Another 1.0 equivalent of Raney nickel was added to the solution and heated at 75 °C overnight. HPLC monitoring showed about 94% conversion. The heating was stopped and the reaction mixture was cooled, diluted with MeOH and filtered through celite, and washed with MeOH to remove 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 pale yellow solid as the desired product tert-butyl 4-(4-formyl-3-methoxy-carbonylphenyl)piperazine-1-carboxylate (5.00 g, 61.1%). C 18 H 25 N2O5 (M+H) + LCMS calculated for m / z: 349.2; found: 348.9. 1 H NMR (300 MHz, CDCl3) δ 10.34 (s, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 1.6 Hz, 1H), 7.00 (dd, J = 8.8, 2.6 Hz, 1H), 3.96 (s, 3H), 3.66 – 3.55 (m, 4H), 3.39 (dd, J = 13.4, 8.6 Hz, 4H), 1.48 (s, 9H).

[0505] Step 3: (S)-tert-butyl 4-(2-(1-amino-5-methoxy-1,5-dioxopentan-2-yl)-3-oxoisoindolin-5-yl)piperazine-1-carboxylate

[0506]

[0507] 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 mixture was stirred at room temperature for 1 h and acetic acid (6.89 mL, 121 mmol) was added to this solution. The reaction mixture was stirred for an additional hour and sodium triacetoxyborohydride (7.66 g, 36.2 mmol) was added. The reaction mixture was stirred overnight to check for complete conversion, monitored by HPLC. The reaction mixture was diluted with DCM (30.0 mL) and quenched with water (30.0 mL). Further extraction was carried out with DCM (30 mL x 2). The organic phase was dried over Na2SO4, filtered, and concentrated to afford the crude product. The crude product was further purified by FCC (0% to 7% MeOH / DCM) to afford the desired compound as a white solid, tert-butyl (S)-4-(2-(1-amino-5-methoxy-1,5-dioxopentan-2-yl)-3-oxoisoindolin-5-yl)piperazine-1-carboxylate (3.80 g, 68.5%). C 23 H 33 N4O6 (M+H) + LCMS calculated for m / z: 461.2; found: 461.1. 1 H NMR (300 MHz, CDCl3) δ 7.33 (dd, J = 10.8,5.3 Hz, 2H), 7.16 (dd, J = 8.4, 2.4 Hz, 1H), 6.40 (s, 1H), 5.58 (s, 1H), 5.00– 4.83 (m, 1H), 4.39 (q, J = 16.8 Hz, 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, 8.2 Hz, 1H),1.49 (s, 9H).

[0508] Step 4: tert-butyl (S)-4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazine-1-carboxylate

[0509]

[0510] At -78 °C, potassium tert-butoxide (1.0 M in THF, 9.90 mL, 9.90 mmol) was added 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). The reaction mixture was stirred at -78 °C for 3 h. The reaction temperature was maintained at 0 °C and quenched by the addition of 1N HCl to pH 3. NaHCO3 (saturated aqueous solution) was slowly added dropwise to this solution to 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 Na2SO4, filtered and concentrated to afford the crude product. tert-Butyl (S)-4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazine-1-carboxylate (2.90 g, 82.0%). The crude product was ~96% pure (HPLC) and was carried on to the next step without further purification. C 18 H 21 N4O5 (M+2H- t Bu) + LCMS calculated for m / z: 373.2; found: 373.0. 1H NMR (300 MHz, CDCl3) δ 8.06 (s, 1H), 7.37 (dd, J = 9.3, 5.3 Hz, 2H), 7.17 (dd, J = 8.4, 2.3 Hz, 1H), 5.22 (dd, J = 13.1, 5.2 Hz, 1H), 4.35 (dd, J = 43.1, 15.6 Hz, 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).

[0511] Step 5: (S)-3-(1-Oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

[0512]

[0513] At 0 °C, a solution of 4 N HCl in dioxane (34.0 mL, 136 mmol) was added 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). The solution was stirred from 0 °C to room temperature for 3 h to check for 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 (3.30 g, 90.1%). C 17 H 21 N4O3 (M+H) + LCMS calculated for m / z: 329.2; found: 329.0. 1 H NMR (300 MHz, DMSO) δ 10.98 (s, 1H), 9.27 (s, 2H), 7.49 (d, J = 8.3 Hz, 1H), 7.39 – 7.19 (m, 2H), 5.10 (dd, J = 13.2, 5.1 Hz, 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 = 16.3 Hz, 1H), 2.46 – 2.27 (m, 1H), 2.09 – 1.94 (m, 1H).

[0514] Intermediates 8a and 8b: (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

[0515]

[0516] Step 1: 1-(tert-Butyl) 2-methyl (4R)-4-(benzyloxy)-2-ethylpyrrolidine-1,2-dicarboxylate

[0517]

[0518] At -78 °C, LiHMDS (12 mL, 12 mmol) was slowly added to a solution of (2R,4R)-4-(benzyloxy)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (2.00 g, 5.96 mmol) in THF (55 mL). The reaction mixture was stirred at -78 °C for 1 h, after which iodoethane (1.9 mL, 23.6 mmol) was added. The reaction solution was stirred at -78 °C for 5 min and then slowly warmed to room temperature with stirring. After 3.5 h, the reaction solution 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 min and then poured into water. The aqueous layer was extracted with EtOAc (3 x). The combined organic layers were washed with brine (1 x), then concentrated and purified by SiO2 FCC (0-30% EtOAc / hexane) to give (4R)-4-(benzyloxy)-2-ethylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (1.11 g, 51%). C 15 H 22 NO3 [M−Boc+2H] + LCMS calculated for m / z: 264.2; found: 264.0.

[0519] Step 2: (4R)-4-(Benzyloxy)-1-(tert-butoxycarbonyl)-2-ethylpyrrolidine-2-carboxylic acid

[0520]

[0521] To a solution of (4R)-4-(benzyloxy)-2-ethylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (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 solution was stirred at 75 °C for 2.5 h and then cooled to room temperature. The mixture was poured into water and then extracted with MTBE (3 x). The combined organic layers were washed with water (2x). The combined aqueous layers were re-extracted with MTBE once and then acidified to pH < 2 with 2 N HCl (aqueous solution) and subsequently extracted with EtOAc (3x). The combined EtOAc layers were washed with brine, dried over MgSO4, filtered and then concentrated to give the crude product (4R)-4-(benzyloxy)-1-(tert-butoxycarbonyl)-2-ethylpyrrolidine-2-carboxylic acid as a yellow oil (assumed quantitative yield). C 14 H 20 NO3 [M−Boc+2H] +Calculated LCMS value of m / z: 250.1; Experimental value: 250.0.

[0522] Step 3: (2R,4R)-4-(Benzyloxy)-2-((4-bromo-6-chloropyridazin-3-yl)carbamoyl)-2-ethylpyrrolidine-1-carboxylic acid tert-butyl ester and (2S,4R)-4-(Benzyloxy)-2-((4-bromo-6-chloropyridazin-3-yl)carbamoyl)-2-ethylpyrrolidine-1-carboxylic acid tert-butyl ester

[0523]

[0524] To a solution of the crude product (4R)-4-(Benzyloxy)-2-ethylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (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 mixture was stirred at room temperature for 20 minutes and then concentrated. The residue was dissolved in THF (8 mL), then 4-bromo-6-chloropyridazin-3-amine (802 mg, 3.85 mmol) was added, followed by NaH (60% dispersed in mineral oil; 385 mg, 9.62 mmol). After rinsing the sides of the flask with THF (2 mL), the reaction mixture was stirred at room temperature for 50 minutes and then cooled to 0 °C and quenched with saturated NH4Cl (aqueous solution). The mixture was poured into water and then extracted with EtOAc (3 x). The combined organic layers were washed with brine (1 x) and then concentrated. The residue was purified by SiO2 FCC (0-100% EtOAc / hexane) to give "diastereomer A" (2R,4R)-4-(Benzyloxy)-2-((4-bromo-6-chloropyridazin-3-yl)carbamoyl)-2-ethylpyrrolidine-1-carboxylic acid tert-butyl ester (473 mg, 46%) and "diastereomer B" (2S,4R)-4-(Benzyloxy)-2-((4-bromo-6-chloropyridazin-3-yl)carbamoyl)-2-ethylpyrrolidine-1-carboxylic acid tert-butyl ester (286 mg, 28%). C 23 H 29 BrClN4O4 [M+H] + Calculated LCMS value of m / z: 539.1; Experimental value: 539.0 (diastereomer A) and 539.0 (diastereomer B).

[0525] 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

[0526] To a solution of (2R,4R)-4-(benzyloxy)-2-((4-bromo-6-chloropyridazin-3-yl)carbamoyl)-2-ethylpyrrolidine-1-carboxylic acid tert-butyl ester (473 mg, 0.88 mmol) in DCM (17 mL) was added TFA (17 mL, 222 mmol). The reaction mixture was stirred at room temperature for 3 h 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 mixture was stirred at 80 °C for 2 h and then cooled to room temperature overnight. The reaction mixture was concentrated to afford the crude product (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; assumed 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 by SiO2 FCC (0:20:80 to 60:20:40 EtOAc / DCM / hexane). C 18 H 20 ClN4O2 [M +H] + LCMS calculated value for m / z: 359.1; experimental value: 359.1.

[0527] 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

[0528]

[0529] 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

[0530]

[0531] At 0 °C, BH3·Me2S (2 M in THF; 5 mL, 10 mmol) was added 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). The reaction mixture was stirred at 55 °C for about 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), then treated with NaBH3CN (0.8 g, 12.7 mmol) in two portions. The reaction was warmed to room temperature and then stirred at 70 °C for 6 h, after which the reaction was cooled to room temperature and concentrated. The residue was diluted with DCM and saturated NaHCO3 (aqueous solution) and extracted with DCM (3 x). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude material was purified by SiO2 FCC (0 - 20% MeOH / DCM) to afford (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%). C 18 H 22 ClN4O [M+H] + LCMS calculated for m / z: 345.1; found: 345.0.

[0532] 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

[0533]

[0534] At 0 °C, BCl3 (1 M in DCM; 10 mL, 10 mmol) was added to a solution of (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). The reaction mixture was stirred at 0 °C for 1.5 h and then quenched slowly with saturated NaHCO3 (aqueous solution). The mixture was poured into water, neutralized with additional saturated NaHCO3 (aqueous solution), and then extracted with DCM (3 x). The combined organic layers were washed with brine (1 x), dried over MgSO4, filtered, and concentrated. The residue was dissolved in MTBE and then sonicated and filtered to afford (6aR,8R)-2-chloro-6a-ethyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol as a white solid (740 mg, 84%). C 11 H 16 ClN4O [M+H] + LCMS calculated for m / z: 255.1; found: 255.0.

[0535] 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

[0536]

[0537] 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, ca. 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 mixture was stirred at 65 °C for 25 min and then cooled to room temperature. The mixture was filtered and the resulting filtrate was purified by SiO2 FCC (0 - 10% MeOH / DCM) to afford (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 as a yellow solid (assumed quantitative yield). C 18 H 19ClN5O4 [M+H] + Calculated LCMS value for m / z: 404.1; Experimental value: 404.0.

[0538] 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

[0539] To a solution of (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 an aqueous solution of NaOH (802 mg, 1.18 mmol) (9 mL). The reaction mixture was stirred at room temperature for 15 minutes, then diluted with a small amount of water and subsequently extracted in bulk with DCM (3 x). The combined organic layers were washed with brine (1 x), then dried over MgSO4, filtered and concentrated. The residue was dissolved in MTBE and the resulting mixture was filtered through a 0.45 µm PTFE sintered filter. The collected solid was washed with MTBE and dried to give the title compound as a white solid (Intermediate 9; 548 mg, 75%). C 11 H 16 ClN4O [M+H] + Calculated LCMS value for m / z: 255.1; Experimental value: 255.0.

[0540] 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

[0541]

[0542] 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

[0543]

[0544] (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'-bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane (744 mg, 0.9 mmol), and potassium carbonate (2.1 g, 15.2 mmol) in a mixture of dioxane (25.0 mL) and water (7.0 mL) were sparged with N2 for about 5 minutes. The reaction mixture was stirred at 100 °C and monitored by LCMS. After 3 hours, the reaction mixture was again subjected to an equal amount of all reagents, sparged with N2 for 5 minutes, and then reheated at 100 °C for an additional hour. The reaction mixture was then cooled to room temperature and poured into water. Extracted with EtOAc (3x), then dried over MgSO4, filtered, and concentrated. The crude product was purified by SiO2 FCC: 0 - 100% EtOAc / hexanes to afford the title compound as an orange foam (1.11 g, 82% yield). C 25 H 26 FN4O3 [M+H] + LCMS calculated for m / z: 449.2; found: 449.1.

[0545] 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

[0546]

[0547] At 0 °C, lithium aluminum hydride (1 M in THF, 5.3 mL, 5.3 mmol) was added dropwise to a solution of (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 (393 mg, 0.88 mmol) in THF (5.00 mL). The reaction mixture was warmed to ambient temperature. After 2 h, additional lithium aluminum hydride (1.50 mL, 1.50 mmol) was added. After 1 h, the reaction mixture was cooled to 0 °C, then methanol (8.0 mL) was added dropwise, followed by acetic acid (1.5 mL, 26.3 mmol) dropwise. The reaction mixture was warmed to ambient temperature, then sodium cyanoborohydride (551 mg, 8.8 mmol) was added and the mixture was stirred at 80 °C overnight. The reaction mixture was then neutralized with saturated NaHCO3 (aqueous solution), then poured into water and extracted with EtOAc (3x). The combined organic layers were washed with brine (1 x), dried over MgSO4, filtered and concentrated. Purification by SiO2 FCC: 0-10% MeOH / DCM gave the title compound as a beige solid (347 mg, 91% yield). C 25 H 28 FN4O2 [M+H] + LCMS calculated for m / z: 435.2; found: 435.1.

[0548] 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

[0549]

[0550] At -78 °C, boron trichloride (6.63 mL, 6.63 mmol) (lower side of the flask) was slowly added to a solution of (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). After complete addition, the reaction mixture was stirred for about 2 minutes and then warmed to 0 °C (ice-water bath). After 20 minutes, the reaction was quenched by dropwise addition of water at 0 °C and neutralized with saturated NaHCO3 (aqueous solution), then extracted with DCM (3 x). The DCM layers were combined, dried over MgSO4, filtered and concentrated. The crude product was purified by SiO2 FCC: 0 - 20% MeOH / DCM to afford the title compound (551 mg, 72%). C 18 H 22 FN4O2 [M+H] + LCMS calculated for m / z: 345.2; found: 345.1.

[0551] 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

[0552] Diisopropyl azodicarboxylate (858 μL, 4.36 mmol) was added 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 (500.0 mg, 1.45 mmol) and triphenylphosphine (2.72 g, 4.36 mmol, 1.6 mmol / g polymer-bound) in THF (20.0 mL). The reaction was stirred at 65 °C and monitored by LC-MS. After 1.5 h, the reaction mixture was cooled and filtered to remove triphenylphosphine, rinsed with THF (20 mL) and then with methanol (40 mL). Potassium carbonate (815 mg, 5.90 mmol) was added to the filtrate and the suspension was stirred for 2 h. The reaction was diluted with DCM and saturated sodium bicarbonate (aqueous solution). The organic layer was separated and the aqueous layer was extracted with DCM 1x and then with EtOAc 1x. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The crude product was purified by SiO2 (0 - 20% MeOH / DCM) to afford the desired product as a white solid (330 mg, 66% yield). C18 H 22 FN4O2 [M+H] + LCMS calculated value of m / z: 345.2; experimental value: 345.0.

[0553] 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

[0554]

[0555] The title compound was prepared according to the procedure for Intermediate 10, starting from Intermediate 8b. C 18 H 22 FN4O2 [M+H] + LCMS calculated value of m / z: 345.2; experimental value: 345.0.

[0556] 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

[0557]

[0558] Step 1: (2R,4S)-4-(benzyloxy)-N-(4-bromo-6-chloropyridazin-3-yl)-2-methylpyrrolidine-2-carboxamide

[0559]

[0560] NaH (60% in mineral oil, 2.76 g, 68.9 mmol) was added portionwise 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). The reaction mixture was stirred until no starting material was consumed. Thereafter, another portion of 60% NaH (0.5 equivalent) was added and HPLC showed a significant improvement in the 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 x 5). 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. C 17 H19 BrClN4O2 [M+H] + LCMS calculated value of m / z: 427.03; experimental value: 427.2.

[0561] 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

[0562]

[0563] 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 the mixture was stirred at ambient temperature for 12 h. The reaction mixture was concentrated and diluted with 100 mL of heptane. The solid was filtered and washed with water to give a white solid. The solid was dissolved in DCM and saturated Na2CO3 (aqueous solution), then separated. The aqueous layer was extracted again with DCM (3x). The organic layers were combined, filtered through a silica gel layer and concentrated to give the title compound (8.5 g, 54% yield). The crude product was used in the next step without further purification. C 17 H 18 ClN4O2 [M+H] + LCMS calculated value of m / z: 345.1; experimental value: 345.5.

[0564] 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

[0565]

[0566] At 0 °C, BH3·DMS (18.1 mL, 191 mmol) was added 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). The reaction mixture was warmed to room temperature and stirred at 50 °C for 90 minutes. Once completed by LCMS, the reaction mixture was cooled to 0 °C and quenched by dropwise addition of methanol. The reaction mixture was concentrated and then dissolved in EtOH (60 mL). At 0 °C, NaBH3CN (11.9 g, 191 mmol) and acetic acid (21.8 mL, 381 mmol) were added to this solution. The reaction mixture was slowly heated to 80 °C and stirred overnight. The reaction mixture was cooled to room temperature, poured into saturated NaHCO3 (aqueous solution) 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 / (EtOAc with 1% MeOH) to afford the title compound as a colorless solid (5.3 g, 6% yield). C 17 H 20 ClN4O [M+H] + LCMS calculated value for m / z: 331.1; experimental value: 331.5.

[0567] 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

[0568] At -78 °C, boron trichloride (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). The resulting mixture was stirred at -78 °C for 30 minutes and quenched with MeOH (10 mL). The volatiles were evaporated and the residue was basified by addition of 10% Na2CO3 solution and then extracted with CHCl3 / IPA (3:1, 10 mL × 6). The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was dried under high vacuum to afford the title compound as a white solid (140 mg, 95% yield). The crude product was used in the next step without further purification. C 10 H 14 ClN4O [M+H]+ LCMS calculated value of m / z: 241.1; experimental value: 241.3.

[0569] 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

[0570]

[0571] 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

[0572] The title compound was synthesized according to the procedure described for Intermediate 12. C 10 H 14 ClN4O [M+H] + LCMS calculated value of m / z: 241.1; experimental value: 241.2.

[0573] 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

[0574]

[0575] The title compound was synthesized according to a procedure similar to that described for Intermediate 12, using "Diastereomer B" from Example 55, Step 5. C 10 H 14 ClN4O [M+H] + LCMS calculated value of m / z: 241.1; experimental value: 241.2.

[0576] 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

[0577]

[0578] 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-hydroxy-phenyl-boronic acid (518 mg, 3.32 mmol), K3PO4 (1.06 g, 4.99 mmol) and XPhos Pd G2 (65 mg, 0.08 mmol) in 1,4-dioxane (6.00 mL) and water (0.30 mL) was purged with N2 for 2 minutes. The reaction mixture was stirred overnight at 100 °C. The reaction mixture was poured into saturated NaHCO3 (aqueous) solution and extracted with CHCl3 / IPA (3:1, 5x). The combined organic phases were dried over Na2SO4. After removal of the solvent, the residue was purified by SiO2 FCC 0-10% MeOH / DCM to afford the title compound as a yellow solid (160 mg, 61% yield). C 16 H 18 FN4O2[M+H] + LCMS calculated for m / z: 317.1; found: 317.5.

[0579] Intermediate 16: 5-(Trifluoromethyl)-6-vinylpyridin-3-ol

[0580]

[0581] 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 N2 for 5 minutes, then SPhos Pd G2 (220 mg, 0.31 mmol) was added, the reaction mixture was sealed with a septacap, purged with N2 for an additional 5 minutes and then stirred at 95 °C. After 5 h, the reaction mixture was cooled to room temperature, filtered through celite, concentrated and then purified using SiO2 FCC 0-20% MeOH / DCM to afford the title compound (280 mg, 59% yield). C8H7F3NO [M+H] + LCMS calculated for m / z: 190.1; found: 190.0.

[0582] Intermediate 17: 6-Fluoro-4-iodonicotinic acid

[0583]

[0584] At -78 °C, LDA (8.9 mL, 17.7 mmol) was added dropwise to a solution of 6-fluoronicotinic acid (1.0 g, 7.09 mmol) in THF (14.0 mL). The reaction mixture was stirred at -78 °C for 10 minutes and then at -50 °C for 90 minutes. The reaction mixture was returned to -78 °C, and 4.0 mL of THF containing iodine (1.80 g, 7.09 mmol) was added dropwise. The reaction mixture was stirred at -50 °C for 1 hour and then quenched by adding 3.0 mL of THF containing acetic acid (2.84 mL, 49.6 mmol) at -78 °C. The resulting mixture was poured into 10% citric acid solution and extracted with EtOAc (3x). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC on a C18 column (30 x 250 mm, 10 µM) using a mobile phase of 8 - 55% MeCN / H2O (with 0.1% TFA) (tR = 18 minutes). 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). C6H4FINO2 [M+H] + LCMS calculated value for m / z: 267.9; experimental value: 268.2.

[0585] Intermediate 18: 5-Fluoro-6-vinylpyridin-3-ol

[0586]

[0587] A mixture of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (500 uL, 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 about 10 minutes and then stirred at 80 °C overnight. The reaction mixture was cooled to room temperature, then filtered through celite and rinsed with MeOH. The filtrate was concentrated, dissolved in DCM, and then purified by SiO2 FCC: 0 - 100% EtOAC / hexane to give the title compound as a yellow oil (300 mg, quantitative yield). C7H7FNO [M+H] + LCMS calculated value for m / z: 140.1; experimental value: 139.9.

[0588] Intermediate 19: 5-Hydroxy-3,6-dimethylpyridinecarbonitrile

[0589]

[0590] Step 1: 6-Bromo-2,5-dimethylpyridin-3-ol

[0591]

[0592] Dissolve 6-bromo-2,5-dimethylpyridin-3-amine (1.0 g, 4.97 mmol) in water (9.0 mL) and sulfuric acid (2.5 mL, 4.97 mmol). Cool the solution to 0 °C and add sodium nitrite (686 mg, 9.95 mmol) portionwise over 10 minutes. Stir the solution at room temperature for 5 minutes and then at 90 °C for 1 - 2 hours or until complete consumption of the starting material is confirmed by LCMS. Cool the reaction mixture to room temperature and carefully neutralize to pH ~7 - 8 with saturated NaHCO3 (aqueous solution). Wash the aqueous layer with brine and extract with EtOAc (4x). Dry the combined organic layers over Na2SO4 and concentrate to dryness to afford the title compound (850 mg, 72% yield). The crude product can be used in the next step without further purification. C7H9BrNO [M+H] + LCMS calculated for m / z: 202.0; found: 202.1.

[0593] Step 2: 5-Hydroxy-3,6-dimethylpyridinecarbonitrile

[0594] Dissolve 6-bromo-2,5-dimethylpyridin-3-ol (720 mg, 3.56 mmol) and copper(I) cyanide (638 mg, 7.13 mmol) in DMF (11.8 mL) and degas the resulting mixture by sparging with nitrogen. Heat the mixture at 130 °C for 3 hours. After cooling to room temperature, dilute the reaction mixture with EtOAc and wash with brine. Re-extract the aqueous layer with EtOAc 2x and dry the combined organic layers over Na2SO4 and concentrate to dryness. Dissolve the crude mixture in DMSO and centrifuge to remove any undissolved solids. Then purify the crude mixture by reverse phase preparative HPLC 10 - 30% ACN / water (with 0.1% TFA) to afford the title compound (407 mg, 77% yield). C8H9N2O [M+H] + LCMS calculated for m / z: 149.1; found: 149.2.

[0595] Example 1: 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

[0596]

[0597] Step 1: 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

[0598]

[0599] 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 (200 mg, 0.610 mmol, Intermediate 1), polymer-supported triphenylphosphine (0.760 g, 1.22 mmol, 100 - 200 mesh, at a loading of 1.6 mmol PPh3 / g), 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 by SiO2 FCC: 0 - 100% EtOAc / hexane 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. C 21 H 24 ClN4O4 [M+H] + LCMS calculated for m / z: 431.2; found: 431.1.

[0600] Step 2: 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

[0601]

[0602] To a solution of 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 (19.8 mg, 50.0 μmol) in THF (1.00 mL) and water (200 μL) were added dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium(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 N2 for about 2 minutes and then stirred at 100 °C. After 1 hour, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by 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. C 27 H 27 F2N4O5 [M+H] + LCMS calculated for m / z: 525.2; found: 525.0.

[0603] 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

[0604]

[0605] To a solution of 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 afford 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, quant.) as the TFA salt. C 22 H 19 F2N4O3 [M+H]+ LCMS calculated value of m / z: 425.1; experimental value: 425.2.

[0606] Step 4: 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

[0607] To a solution of 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 mixture was sonicated and stirred at 50 °C for 1 h, and then sodium triacetoxyborohydride (13.0 mg, 60.0 μmol) was added. The solution was stirred at 50 °C for 20 min and then at 70 °C for 1.5 h. The reaction mixture was cooled to room temperature, filtered and purified directly by preparative LCMS (7.8 - 25.8% CH3CN / H2O with 0.1% TFA) to give 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 the white TFA salt. C 39 H 39 F2N8O5 [M+H] + LCMS calculated value of m / z: 737.3; experimental value: 737.2.

[0608] Example 2 - 25

[0609] Examples 2 - 25 shown in Table 1 below were prepared as TFA salts using the method for preparing Example 1 with appropriate starting materials and intermediates.

[0610] Table 1. Examples 2 - 25

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619] Example 26: 3-(6-(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)pyrimidin-5-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0620]

[0621] Step 1: 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

[0622]

[0623] Using a procedure similar to that described in Example 1, Step 2, the title compound was prepared using Intermediate 1 in place of 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 and (3,5-difluoro-2-methoxyphenyl)boronic acid in place of (3,5-difluoro-2-hydroxyphenyl)boronic acid. C 21 H 25 F2N4O4 [M+H] + LCMS calculated value for m / z: 435.2; experimental value: 435.1.

[0624] Step 2: 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

[0625]

[0626] 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]pyridazin-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 showed incomplete reaction, and additional triethylamine (479 μL, 3.44 mmol) and methanesulfonyl chloride (249 μL, 3.22 mmol) were added. The reaction solution was concentrated under reduced pressure and purified by SiO2 FCC: 0 - 100% EtOAc / hexane 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]pyridazin-5(6H)-carboxylate (110 mg, quantitative yield). C 22 H 27 F2N4O6S [M+H] + LCMS calculated value for m / z: 513.2; experimental value: 513.1.

[0627] Step 3: 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]pyridazin-5(6H)-carboxylate

[0628]

[0629] A mixture of 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 (44.0 mg, 85.8 μmol), 2-thiopyrimidine-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 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, filtered, and concentrated under reduced pressure. The crude material was purified by SiO2 FCC: 0 - 100% EtOAc / hexane 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. C 26 H 27 F2N6O4S [M+H] + LCMS calculated for m / z: 557.2; found: 557.1.

[0630] 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

[0631]

[0632] 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 mixture was stirred at room temperature for 48 h. The reaction mixture was carefully poured into a saturated aqueous solution of NaHCO3, and the aqueous phase was extracted with DCM. The combined organic layers were washed with a saturated brine solution, dried over MgSO4, filtered, and concentrated under reduced pressure to afford the title compound (10.6 mg, 61% yield) as a pale yellow solid. C 20 H 17 F2N6O2S [M+H] +Calculated LCMS value of m / z: 443.1; Experimental value: 442.9.

[0633] Step 5: 3-(6-(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)pyrimidin-5-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0634] 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 mixture was stirred at 80 °C for 4 h. The reaction mixture was cooled to room temperature, diluted with MeOH and filtered. The filtrate was purified directly by preparative HPLC (Waters CSH-C18, 5 uM, 30 x 100 mm, 6.5 - 24.5% MeCN / water (containing 0.1% TFA), within 5 min) to afford the TFA salt of the title compound as a white solid (1.2 mg, 5.1% yield). C 37 H 37 F2N 10 O4S[M+H] + Calculated LCMS value of m / z: 755.3; Experimental value: 755.2.

[0635] 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

[0636]

[0637] Step 1: 4-Methyl-5-vinylpyridin-2-ol

[0638]

[0639] 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'-bis(diphenylphosphino)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 solution was heated at 100 °C for 1 hour. The reaction solution was cooled to room temperature, quenched with a saturated aqueous solution of NH4Cl (1.00 mL), filtered, and concentrated under reduced pressure. The crude material was purified by SiO2 FCC: 0 - 5% MeOH / DCM to obtain 4-methyl-5-vinylpyridin-2-ol (108 mg, quantitative yield). C8H 10 NO [M+H] + LCMS calculated value for m / z: 136.1; experimental value: 136.0.

[0640] 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]pyridazin-5(6H)-carboxylic acid tert-butyl ester

[0641]

[0642] Diisopropyl azodicarboxylate (169 μL, 857 μmol) was added to a solution of (6aR,8S)-2-chloro-8-hydroxy-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-5(6H)-carboxylic acid tert-butyl ester (70.0 mg, 214 μmol, Intermediate 1), 4-methyl-5-vinylpyridin-2-ol (107 mg, 793 μL), and triphenylphosphine (225 mg, 857 μmol) in THF (2.00 mL), and the reaction mixture was heated at 60 °C for 30 minutes. The reaction solution was cooled to room temperature and purified directly by SiO2 FCC: 0 - 100% EtOAC / hexane to obtain (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]pyridazin-5(6H)-carboxylic acid tert-butyl ester (95.1 mg, quantitative yield). C 22 H 27 ClN5O3 [M+H] +LCMS calculated value of m / z: 444.2 / 446.2; experimental value: 444.1 / 446.2.

[0643] Step 3: 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

[0644]

[0645] 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 mixture was stirred at room temperature overnight. The reaction mixture 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 obtain the crude product 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 subsequent step without further purification. C 21 H 25 ClN5O4 [M+H] + LCMS calculated value of m / z: 446.2; experimental value: 446.1.

[0646] Step 4: tert-Butyl (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

[0647]

[0648] Using a procedure similar to that described in Step 2 of Example 1, the title compound was prepared using 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 instead of 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 and (3,5-difluoro-2-methoxyphenyl)boronic acid instead of (3,5-difluoro-2-hydroxyphenyl)boronic acid. C 28 H 30 F2N5O5 [M+H] + LCMS calculated value for m / z: 554.2; experimental value: 554.2.

[0649] Step 5: tert-butyl (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

[0650]

[0651] 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-tetrahydropyrrolo[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 mixture was stirred at room temperature for 30 minutes. The reaction was quenched with a saturated aqueous solution of NH4Cl and extracted with DCM. The combined organic layers were washed with a saturated brine solution, dried over MgSO4, filtered and concentrated under reduced pressure to afford the crude product tert-butyl (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 (119 mg, quantitative yield). The material was used in the subsequent step without further purification. C 28 H 32 F2N5O5 [M+H] + LCMS calculated value for m / z: 556.2; experimental value: 556.2.

[0652] Step 6: 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]pyridazin-5(6H)-carboxylate

[0653]

[0654] Using a procedure similar to that described in Step 2 of Example 26, the title compound was prepared using the crude product tert-butyl (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]pyridazin-5(6H)-carboxylate in place of (6aR,8S)-2-(3,5-difluoro-2-methoxyphenyl)-8-hydroxy-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-5(6H)-carboxylate. C 28 H 31 ClF2N5O4 [M+H] + LCMS calculated value for m / z: 574.2 / 576.2; experimental value: 574.2 / 576.1.

[0655] Step 7: tert-Butyl (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]pyridazin-5(6H)-carboxylate

[0656]

[0657] 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 produced. N,N-Diisopropylethylamine (7.94 μL, 45.6 μmol) and MeCN (1.00 mL) were added, and the reaction mixture was stirred at 120 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford the crude product tert-butyl (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. C 45 H 50 F2N9O7 [M+H] + LCMS calculated for m / z: 866.4; found: 866.4.

[0658] Step 8: 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

[0659] Using a procedure similar to that described in Example 26, Step 4, the title compound was prepared using tert-butyl (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 instead 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. C39 H 40 F2N9O5 [M+H] + LCMS calculated value of m / z: 752.3; experimental value: 752.3.

[0660] Examples 28 - 31

[0661] Examples 28 - 31 shown in Table 2 below were prepared as TFA salts using the method for preparing Example 27 with appropriate starting materials and intermediates.

[0662] Table 2. Examples 28 - 31

[0663]

[0664]

[0665]

[0666] 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

[0667]

[0668] The title compound was prepared using a procedure similar to that described in Steps 2 - 3 of Example 26 and Steps 2 - 4 of Example 1 with appropriate starting materials and intermediates. C 39 H 39 F2N8O4S [M+H] + LCMS calculated value of m / z: 753.3; experimental value: 753.2.

[0669] 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

[0670]

[0671] The title compound was prepared using a procedure similar to that described in Steps 2 - 3 of Example 27 and Steps 2 - 4 of Example 1 with appropriate starting materials and intermediates. C38 H 38 F2N9O5 [M+H] + LCMS calculated value of m / z: 738.3; experimental value: 738.2.

[0672] 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

[0673]

[0674] Step 1: 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

[0675]

[0676] Using a procedure similar to the one described in Step 2 of Example 26, the title compound was prepared using 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 (Intermediate 1) instead 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. C 15 H 22 ClN4O5S [M+H] + LCMS calculated value of m / z: 405.1; experimental value: 405.0.

[0677] Step 2: 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

[0678]

[0679] A mixture 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 (265 mg, 655 μL) and sodium cyanide (96.2 mg, 1.96 mmol) in DMSO (500 μL) was stirred overnight at 80 °C. The mixture was cooled to room temperature and diluted with DCM and washed with water. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by SiO2 FCC: 0 - 100% EtOAC / hexane to afford 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). C 15 H 19 ClN5O2 [M+H] + LCMS calculated for m / z: 336.1; found: 336.1.

[0680] Step 3: 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

[0681]

[0682] Using a procedure similar to that described in Example 1, Step 2, the title compound was prepared using 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 in place of 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 and 5-fluoro-2-hydroxyphenylboronic acid in place of (3,5-difluoro-2-hydroxyphenyl)boronic acid. C 21 H 23 FN5O3 [M+H] + LCMS calculated for m / z: 412.2; found: 412.1.

[0683] 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

[0684]

[0685] 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 mixture was stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature, filtered, diluted with MeOH, and the filtrate was purified directly by preparative HPLC (Waters CSH-C18, 5 μM, 30 x 100 mm, 8.1 - 28.1% MeCN / water (containing 0.1% TFA) in 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). C 16 H 16 FN4O3 [M+H] + LCMS calculated for m / z: 331.1; found: 330.9.

[0686] Step 5: 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

[0687]

[0688] 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), tert-butyl (3R,5S)-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 h and treated with 11.6 M aqueous HCl (1.00 mL, 11.6 mmol). The reaction mixture was filtered, diluted with MeOH, and the filtrate was purified directly by preparative HPLC (Waters CSH-C18, 5 μM, 30 x 100 mm, 24.9 - 44.9% MeCN / water (containing 0.1% TFA) in 5 min) to afford the TFA salt of the title compound, 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 (1.60 mg, 6.3% yield). C 27 H 36 FN6O4 [M+H] + LCMS calculated for m / z: 527.3; found: 527.2.

[0689] 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

[0690]

[0691] A solution of 4 N HCl 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]pyridazin-8-carbonyl)-3,5-dimethylpiperazine-1-carboxylate (11.6 mg, 3.04 μmol) in DCM (1.00 mL). The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure to afford 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). C 22 H 28 FN6O2 [M+H] + LCMS calculated for m / z: 427.2; found: 427.2.

[0692] 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]pyridazin-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0693] Using a procedure similar to that described in Example 26, Step 5, the title compound was prepared using ((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; dihydrochloride in place 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 and 1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-4-carbaldehyde (Intermediate 3) in place of 3-(3-oxo-5-piperazin-1-yl-1H-isoindol-2-yl)piperidine-2,6-dione (Intermediate 2). C 41 H 49 FN9O5 [M+H] + LCMS calculated for m / z: 766.4; found: 766.2.

[0694] Example 35: 3-(6-(4-((6-(((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)(methyl)amino)pyridin-3-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0695]

[0696] 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

[0697]

[0698] A solution of 40% 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 Step 1 of Example 34) in ethanol (500 μL). The reaction mixture was stirred at 100 °C overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford (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). C 10 H 15 ClN5 [M+H] + LCMS calculated value for m / z: 240.1; experimental value: 240.1.

[0699] 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

[0700]

[0701] 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 h. The reaction mixture was cooled to room temperature, diluted in MeOH, filtered and purified by preparative HPLC (Waters CSH-C18, 5 uM, 30 x 100 mm, 6.4 - 26.4% MeCN / water (containing 0.1% TFA), over 5 min) to afford the TFA salt of 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 (15.0 mg, 75% yield). C 16 H 18 ClN6O [M+H] + LCMS calculated for m / z: 345.1; found: 345.1.

[0702] 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

[0703] The title compound was prepared using a procedure similar to that described in Example 1, Steps 2 and 4, using the appropriate starting materials and intermediates. C 39 H 42 FN 10 O4 [M+H] + LCMS calculated for m / z: 733.3; found: 733.3.

[0704] 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

[0705]

[0706] Step 1: (2S,4R)-2-(Azidomethyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine

[0707]

[0708] Add 2,2,2-trifluoroacetic acid (5.00 mL, 65.3 mmol) 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 in step 4 for intermediate 1) in DCM (6.00 mL). Stir the reaction mixture at room temperature for 1 h. Alkalize the reaction mixture to pH ~12 with 2N aqueous NaOH. Separate the layers and extract the aqueous phase with DCM (3 x 25.0 mL). Wash the combined organic layers with saturated brine solution, dry over MgSO4, filter and concentrate under reduced pressure to obtain (2S,4R)-2-(azidomethyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine (900 mg, 89% yield). The material was used in the subsequent step without further purification. C 11 H 25 N4OSi [M+H] + LCMS calculated for m / z: 257.2; found: 257.1.

[0709] Step 2: (6aS,8R)-2-Chloro-8-hydroxy-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-5(6H)-carboxylic acid tert-butyl ester

[0710]

[0711] The title compound was prepared using a procedure similar to that described in steps 6 to 9 for intermediate 1. C 14 H 20 ClN4O3[M+H] + LCMS calculated for m / z: 327.1 / 329.1; found: 327.8 / 328.9.

[0712] Step 3: (6aS,8S)-2-Chloro-8-((4-nitrobenzoyl)oxy)-6a,7,8,9-tetrahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-5(6H)-carboxylic acid tert-butyl ester

[0713]

[0714] At 0 °C, 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. The reaction mixture was heated to 60 °C and stirred for 1 h. The mixture was cooled to room temperature and quenched with water. The mixture was purified directly by SiO2 FCC: 0 - 100% EtOAC / hexane to afford 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). C 21 H 23 ClN5O6 [M+H] + LCMS calculated value for m / z: 476.1; experimental value: 476.1.

[0715] Step 4: 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

[0716]

[0717] 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 mixture was stirred at room temperature for 1 h. The mixture was diluted with water and then extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by SiO2 FCC: 0 - 10% MeOH / DCM to afford 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). C 14 H 20 ClN4O3 [M+H] +LCMS calculated value of m / z: 327.1; experimental value: 327.1.

[0718] Step 5: 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

[0719] Using a procedure similar to that described in Example 1, Steps 1 to 4, prepare the title compound using appropriate starting materials and intermediates. C 40 H 42 FN8O5 [M+H] + LCMS calculated value of m / z: 733.3; experimental value: 733.2.

[0720] Example 37

[0721] Prepare Example 37 shown in Table 3 below as the TFA salt using a method for preparing Example 36 and appropriate starting materials and intermediates.

[0722] Table 3. Example 37

[0723]

[0724] 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

[0725]

[0726] 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)-carboxylic acid tert-butyl ester

[0727]

[0728] Using a procedure similar to that described in Example 26, Steps 2 - 3, prepare the title compound using appropriate intermediates and starting materials. C 21 H 25 ClN5O3S [M+H] +LCMS calculated value of m / z: 462.1 / 464.1; experimental value: 462.1 / 464 / 1.

[0729] 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

[0730] Using a procedure similar to that described in Example 27, Steps 4 - 7 and Example 26, Step 4, the title compound was prepared using the appropriate intermediates and starting materials. C 39 H 40 F2N9O4S [M+H] + LCMS calculated value of m / z: 768.3; experimental value: 768.2.

[0731] 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

[0732]

[0733] 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)-carboxylic acid tert-butyl ester

[0734]

[0735] 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 (100 mg, 0.247 mmol, intermediate from Step 1 of Example 34), tert-butyl 4-hydroxypyrazole-1-carboxylate (182 mg, 0.988 mmol), and potassium carbonate (172 mg, 1.24 mmol) in a mixture of NMP (2.00 mL) were stirred overnight at 100 °C. The reaction mixture was cooled to room temperature, diluted with water, and the aqueous phase was extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to afford 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-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-1H-pyrazole-1-carboxylate (122 mg). C 22 H 30 ClN6O5 [M+H] + LCMS calculated for m / z: 493.2 / 495.2; found: 493.1 / 495.1.

[0736] Step 2: 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

[0737]

[0738] To a 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-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)-1H-pyrazole-1-carboxylate (122 mg, 0.247 mmol) was added NMP (2.00 mL) containing 4-(dimethylamino)pyridine (30.2 mg, 0.247 mmol) and di-tert-butyl dicarbonate (270 mg, 1.24 mmol). The reaction mixture was stirred at room temperature for 1 h. The crude reaction mixture was purified directly by SiO2 FCC: 0 - 100% EtOAC / hexane to afford 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 (122 mg, quantitative yield), C 22 H 30 ClN6O5 [M+H] + LCMS calculated for m / z: 493.2 / 495.2; found: 493.1 / 495.1.

[0739] Step 3: tert-butyl (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

[0740]

[0741] Using a procedure similar to that described in Example 1, Step 2, the title compound was prepared using 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 in place of 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 and (3,5-difluoro-2-methoxyphenyl)boronic acid in place of (3,5-difluoro-2-hydroxyphenyl)boronic acid. C 29 H 35F2N6O6 [M+H] + LCMS calculated value of m / z: 601.3; experimental value: 601.2.

[0742] 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

[0743]

[0744] Add 2,2,2-trifluoroacetic acid (0.835 mL, 10.9 mmol) to a solution of tert-butyl (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 (65.5 mg, 0.109 mmol) in DCM (2.00 mL). Stir the reaction mixture at room temperature for 3 hours. Neutralize the reaction mixture with saturated aqueous NaHCO3 and extract with DCM. Wash the combined organic layers with saturated brine solution, dry over MgSO4, filter and concentrate under reduced pressure to obtain (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 can be used without further purification. C 19 H 19 F2N6O2 [M+H] + LCMS calculated value of m / z: 401.2; experimental value: 401.1.

[0745] 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

[0746]

[0747] Using a procedure similar to the one described in Example 27, Step 7, replace (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]pyridazin-5(6H)-carboxylic acid tert-butyl ester with (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 and 4-methylbenzenesulfonic acid (1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-4-yl) methyl ester (Intermediate 4) with 3-(3-oxo-5-piperazin-1-yl-1H-isoindol-2-yl)piperidine-2,6-dione (Intermediate 2) to prepare the title compound. C 38 H 40 LCMS calculated value for F2N9O5 [M+H]+ m / z: 740.3; experimental value: 740.4.

[0748] 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

[0749] Using a procedure similar to the one described in Example 26, Step 4, replace (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]pyridazin-5(6H)-carboxylic acid tert-butyl ester with 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 to prepare the title compound. C 37 H 38 LCMS calculated value for F2N9O5 [M+H]+ m / z: 726.3; experimental value: 726.3.

[0750] 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

[0751]

[0752] Step 1: (2S,4R)-4-(Benzyloxy)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester

[0753]

[0754] Methyl iodide (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 mixture was stirred at room temperature for 2 h. The product mixture was diluted with EtOAc (200 mL). The diluted product mixture was washed with water (200 mL) and with saturated aqueous sodium chloride (2 x 200 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was used without further purification. (2S,4R)-4-(Benzyloxy)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (6.46 g, 99%) was obtained as a yellow oil. C 13 H 18 NO3 [M+H-C5H9O2] + LCMS calculated value for m / z: 236.1; experimental value: 236.1.

[0755] Step 2: (4R)-4-(Benzyloxy)-2-(difluoromethyl)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester

[0756]

[0757] At -78 °C, lithium bis(trimethylsilyl)amide (1 M in THF, 30 mL, 30 mmol) was added to a stirred solution of methyl (2S,4R)-4-(benzyloxy)pyrrolidine-1,2-dicarboxylate 1-(tert-butyl) 2-ester (6.7 g, 20 mmol) in THF (100 mL). The reaction mixture was slowly warmed for 45 minutes until it reached room temperature. Then the reaction mixture was cooled to -78 °C. At -78 °C, difluoromethyl trifluoromethanesulfonate (5.06 mL, 39.9 mmol) was added dropwise to the reaction mixture. The reaction mixture was slowly warmed to room temperature and stirred overnight. The product mixture was diluted with saturated aqueous ammonium chloride (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 (2 x 200 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel with a gradient of 0 - 50% EtOAc / hexane to afford methyl (4R)-4-(benzyloxy)-2-(difluoromethyl)pyrrolidine-1,2-dicarboxylate 1-(tert-butyl) 2-ester (5.6 g, 73%) as an inseparable mixture of diastereoisomers. C 14 H 18 F2NO3 [M+H-C5H9O2] + LCMS calculated for m / z: 286.1; found: 286.0.

[0758] Step 3: (4R)-4-(Benzyloxy)-1-(tert-butoxycarbonyl)-2-(difluoromethyl)pyrrolidine-2-carboxylic acid

[0759]

[0760] At room temperature, an aqueous sodium hydroxide solution (2.5 M, 58.4 mL, 146 mmol) was added to a stirred solution of methyl (4R)-4-(benzyloxy)-2-(difluoromethyl)pyrrolidine-1,2-dicarboxylate 1-(tert-butyl) 2-ester (5.6 g, 14.5 mmol) in THF (27 mL) and MeOH (27 mL). The reaction mixture was heated to 65 °C and stirred for 2 h. The product mixture was cooled to room temperature and acidified with aqueous hydrochloric acid (1 M, 160 mL, 160 mmol). The acidified product mixture was transferred to a separatory funnel and extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained 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%). C 13 H 16 F2NO3 [M+H-C5H9O2] + LCMS calculated value for m / z: 272.1; experimental value: 271.9.

[0761] Step 4: tert-Butyl (4R)-4-(benzyloxy)-2-((4-bromo-6-chloropyridazin-3-yl)carbamoyl)-2-(difluoromethyl)pyrrolidine-1-carboxylate

[0762]

[0763] 1-[(Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate oxide (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 at room temperature for 40 minutes. The product mixture was concentrated under reduced pressure. The resulting residue was dissolved in THF (62.4 mL). 4-Bromo-6-chloropyridazin-3-amine (4.2 g, 20.2 mmol) was added to the solution and the resulting solution was stirred. At room temperature, sodium hydride (2.2 g, 55.2 mmol, 60% dispersed in mineral oil) was added portionwise to the stirred reaction mixture. After 1 hour, the product mixture was cooled to 0 °C and quenched with saturated aqueous ammonium chloride solution (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 x 200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel with a gradient of 0 - 50% EtOAc / hexane to afford tert-butyl (4R)-4-(benzyloxy)-2-((4-bromo-6-chloropyridazin-3-yl)carbamoyl)-2-(difluoromethyl)pyrrolidine-1-carboxylate (5.4 g, 62%). C 22 H 25 BrClF2N4O4[M+H] + LCMS calculated for m / z: 561.1; found: 561.9.

[0764] 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

[0765]

[0766] At room temperature, 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). The reaction mixture was stirred for 5 h. The product mixture was concentrated under reduced pressure. The residue obtained 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 h. The product mixture was concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel with a gradient of 0-100% EtOAc / hexane to afford (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%). C 17 H 16 ClF2N4O2[M+H] + LCMS calculated for m / z: 381.1; found: 381.0.

[0767] 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

[0768]

[0769] Charge a 20 mL scintillation vial 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) complexed with dichloromethane (129 mg, 0.16 mmol). Dissolve the solid mixture in 1,4-dioxane (8 mL) and water (0.8 mL). Sparge the reaction mixture with N2 gas for 5 minutes, seal, and heat to 100 °C. Stir the reaction mixture at 100 °C for 1 hour. Dilute the product mixture with EtOAc (50 mL). Wash the diluted product mixture with saturated aqueous sodium bicarbonate (50 mL). Extract the aqueous layer with EtOAc (2 x 50 mL). Dry the combined organic layers over Na2SO4, filter, and concentrate under reduced pressure. Purify the obtained residue by flash column chromatography on silica gel with a gradient of 0-100% EtOAc / hexanes to afford (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%). C 24 H 22 F3N4O3[M+H] + LCMS calculated for m / z: 471.2; found: 471.0.

[0770] 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

[0771]

[0772] At 0 °C, 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). 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. At room temperature, acetic acid (770 μL, 13.5 mmol) and sodium cyanoborohydride (428 mg, 6.81 mmol) were sequentially added to the reaction mixture. 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 with saturated potassium carbonate solution (100 mL). The diluted product mixture was extracted with EtOAc (4 x 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel with 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 as a white foamy solid (290 mg, 94%). C 24 H 24 F3N4O2[M+H] + LCMS calculated for m / z: 457.2; found: 457.1.

[0773] 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

[0774]

[0775] At -78 °C, 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). The reaction mixture was warmed to 0 °C and stirred for 30 minutes. The product mixture was quenched with water (5 mL) and transferred to a separatory funnel with saturated aqueous sodium carbonate solution (100 mL). The quenched product mixture was extracted with 3:1 chloroform:isopropanol solution (4 x 100 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel with a gradient of 0 - 20% MeOH / DCM to afford (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%). C 17 H 18 F3N4O2[M+H] + LCMS calculated for m / z: 367.1; found: 367.0. C 16 H 16 F3N4O2[M+H] + LCMS calculated for m / z: 353.1; found: 353.0.

[0776] 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

[0777]

[0778] At 0 °C, sodium hydride (55 mg, 1.38 mmol, 60% dispersed 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). 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 3:1 chloroform:isopropanol solution (3 x 30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel using a gradient of 0 - 15% MeOH / DCM to afford 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%). C 24 H 24 F3N6O4[M+H] + LCMS calculated for m / z: 517.2; found: 517.0.

[0779] 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

[0780]

[0781] At -78 °C, diisobutylaluminum hydride (1.0 M in toluene, 0.81 mL, 0.81 mmol) 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). The reaction mixture was warmed to 0 °C and stirred for 1 h. The reaction mixture was quenched with saturated aqueous sodium potassium 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 x 30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained was dissolved in methanol (3 mL) and cooled to 0 °C. At 0 °C, sodium borohydride (22.8 mg, 0.6 mmol) was added to the reaction mixture and stirred for 30 min. The product mixture was transferred to a separatory funnel containing saturated aqueous ammonium chloride (30 mL) and extracted with 3:1 chloroform:isopropanol solution (3 x 30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel using a gradient of 0-20% MeOH / DCM to afford (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%). C 23 H 24 F3N6O3 [M+H] + LCMS calculated for m / z: 489.2; found: 489.0.

[0782] 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

[0783]

[0784] At 0 °C, 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). The reaction mixture was warmed to room temperature and stirred for 16 h. The product mixture was cooled to 0 °C and quenched with slow addition of water (2 mL). The quenched product mixture was transferred to a separatory funnel with saturated aqueous potassium carbonate solution (30 mL) and extracted with chloroform:isopropanol solution (4 x 30 mL) in 3:1 ratio. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained was dissolved in THF (1 mL). The reaction mixture was cooled to 0 °C. At 0 °C, thionyl chloride (39.3 μL, 0.54 mmol) was added to the reaction mixture. The reaction mixture was warmed to room temperature and stirred for 30 min. The product mixture was diluted with water (10 mL) and transferred to a separatory funnel with saturated aqueous potassium carbonate solution (30 mL) and extracted with chloroform:isopropanol solution (4 x 30 mL) in 3:1 ratio. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to afford 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. C 22 H 21 ClF3N6O2 [M+H] + LCMS calculated value for m / z: 493.1; experimental value: 493.0.

[0785] 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)

[0786]

[0787] At room temperature, 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). The reaction mixture was heated to 120 °C and stirred for 1.5 h. The product mixture was cooled to room temperature, diluted with DMSO, and filtered through celite. The diluted product mixture was purified directly by preparative HPLC (Waters CSH-fluoro-phenyl, 5 μM, 30 x 100 mm, 10.1 - 30.1% MeCN / water (containing 0.1% TFA), in 5 min) to afford 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.

[0788] 11H NMR (400 MHz, MeOD) δ 8.19 (s, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.40– 7.29 (m, 4H), 7.08 (s, 1H), 7.02 (td, J = 8.1, 4.8 Hz, 1H), 6.27 (t, J =55.6 Hz, 1H), 5.87 (t, J = 7.6 Hz, 1H), 5.13 (dd, J = 13.3, 5.2 Hz, 1H), 4.53– 4.34 (m, 4H), 4.08 (d, J = 12.6 Hz, 1H), 4.00 (dd, J = 13.2, 3.0 Hz, 1H),3.26 (d, J = 3.9 Hz, 1H), 2.98 – 2.84 (m, 1H), 2.81 – 2.76 (m, 1H), 2.74 (d,J = 14.8 Hz, 1H), 2.56 (s, 3H), 2.54 – 2.40 (m, 2H), 2.17 (dtd, J = 12.9,5.3, 2.5 Hz, 1H). C 39 H 40 F3N 10 O5 [M+H] + LCMS calculated value of m / z: 785.3; experimental value: 785.1.

[0789] Example 41: 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

[0790]

[0791] Step 1: 5-(((tert-Butyldimethylsilyl)oxy)methyl)-2-chloro-4,6-dimethylpyrimidine

[0792]

[0793] At -78 °C, 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). The reaction mixture was slowly warmed to room temperature over 3 h. The reaction mixture was stirred at room temperature for 1 h. The product mixture was quenched with saturated aqueous sodium potassium tartrate (15 mL) and stirred for 30 min. The quenched product mixture was transferred to a separatory funnel with saturated aqueous sodium potassium tartrate (70 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in DCM (13 mL). Imidazole (305 mg, 4.47 mmol) and tert-butyl dimethylsilyl chloride (506 mg, 3.35 mmol) were added sequentially to the stirred reaction mixture. The reaction mixture was stirred for 30 min. The product mixture was filtered through Celite and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel with a gradient of 0 - 50% EtOAc / hexanes to afford 5-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloro-4,6-dimethylpyrimidine (213 mg, 33%). C 13 H 24 ClN2OSi [M+H] + LCMS calculated for m / z: 287.1; found: 287.0.

[0794] 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

[0795]

[0796] At 0 °C, sodium hydride (11 mg, 0.27 mmol, 60% dispersed in mineral oil) was added to a stirred solution of 5-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloro-4,6-dimethylpyrimidine (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). 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 with saturated aqueous ammonium chloride (35 mL) and extracted with ethyl acetate (3 x 35 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel with a gradient of 0 - 10% MeOH / DCM 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%). C 30 H 40 F3N6O3Si [M+H] + LCMS calculated for m / z: 617.3; found: 617.1.

[0797] 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

[0798]

[0799] At 0 °C, 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)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, 0.037 mmol) in DCM (1 mL). The reaction mixture was warmed to room temperature and stirred for 24 minutes. Another 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 cooled to 0 °C. The product mixture was quenched with water (2 mL). The quenched product mixture was transferred to a separatory funnel containing saturated aqueous potassium carbonate solution (30 mL). The diluted product mixture was extracted with 3:1 chloroform:isopropanol solution (4 x 30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to afford 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.

[0800] 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)

[0801]

[0802] At room temperature, 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, 0.033 mmol) in acetonitrile (1 mL). The reaction mixture was heated to 120 °C and stirred for 1.5 h. The product mixture was cooled to room temperature, diluted with DMSO, and filtered through celite. The diluted product mixture was purified directly by preparative HPLC (Waters CSH-C18, 5 μM, 30 x 100 mm, 10.1 - 30.1% MeCN / water (containing 0.1% TFA), over 5 min) to afford 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.

[0803] 11H NMR (400 MHz, MeOD) δ 7.50 (d, J = 8.3 Hz, 1H), 7.40 – 7.30 (m,4H), 7.09 (s, 1H), 7.02 (td, J = 8.1, 4.8 Hz, 1H), 6.32 (t, J = 55.5 Hz, 1H),5.87 (t, J = 7.1 Hz, 1H), 5.13 (dd, J = 13.3, 5.2 Hz, 1H), 4.53 – 4.33 (m,5H), 4.13 (d, J = 12.7 Hz, 1H), 4.02 (dd, J = 13.2, 2.8 Hz, 1H), 3.25 (d, J =3.5 Hz, 1H), 2.96 – 2.84 (m, 1H), 2.82 – 2.73 (m, 1H), 2.69 (d, J = 12.0 Hz,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 value of m / z: 799.3; experimental value: 799.2.

[0804] 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

[0805]

[0806] Step 1: 5-(((tert-Butyldimethylsilyl)oxy)methyl)-2-chloropyrimidine

[0807]

[0808] At -78 °C, 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). The reaction mixture was slowly warmed to room temperature. The product mixture was quenched with saturated aqueous sodium potassium 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 sodium potassium tartrate (30 mL). The diluted product mixture 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 dissolved in DCM (6 mL). Imidazole (278 mg, 4.09 mmol) and tert-butyldimethylsilyl chloride (308 mg, 2.04 mmol) were added to the reaction mixture in sequence. The reaction mixture was stirred for 30 minutes. The product mixture was filtered through Celite and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel with a gradient of 0 - 50% EtOAc / hexanes to afford 5-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloropyrimidine (210 mg, 64%). C 11 H 20 ClN2OSi [M+H] + LCMS calculated for m / z: 259.1; found: 259.0.

[0809] 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)

[0810]

[0811] This example was synthesized by a procedure similar to that described in Example 41, using 5-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloropyrimidine in place of 5-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloro-4,6-dimethylpyrimidine.

[0812] 11H NMR (400 MHz, MeOD) δ 8.80 (s, 2H), 7.50 (d, J = 8.3 Hz, 1H), 7.39– 7.28 (m, 4H), 7.09 (s, 1H), 7.02 (td, J = 8.0, 4.8 Hz, 1H), 6.30 (t, J =55.5 Hz, 1H), 5.89 (t, J = 7.2 Hz, 1H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.51– 4.31 (m, 5H), 4.12 (d, J = 12.6 Hz, 1H), 4.05 (dd, J = 13.1, 2.9 Hz, 1H),3.48 (br, 7H) 3.30 – 3.24 (m, 1H), 2.96 – 2.84 (m, 1H), 2.80 (dd, J = 4.8,2.5 Hz, 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] + Calculated LCMS value of m / z: 771.3; Experimental value: 771.2.

[0813] 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

[0814]

[0815] Step 1: 5-(1,3-dioxolan-2-yl)-2-fluoropyridine

[0816]

[0817] 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 and then 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 - 10% EtOAc / hexane to afford 5-(1,3-dioxolan-2-yl)-2-fluoropyridine (22.6, 67%). C8H9FNO2 [M+H] + LCMS calculated for m / z: 170.1; found: 170.3.

[0818] 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

[0819]

[0820] 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), and then BF3•Et2O (7.45 g, 52.5 mmol) was added dropwise 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 any further purification. Acetic acid (7.56 g, 125.9 mol) and sodium cyanoborohydride (3.96 g, 62.9 mmol) were added successively 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 water (50 mL) was added to quench the mixture. 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, which was purified by flash column chromatography on silica gel with a gradient of 50 - 100% MTBE / hexane to afford (6aR,8R)-8-(benzyloxy)-2-chloro-6a-(difluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine as a white solid (4.78 g, 99%). C 17 H 18 ClF2N4O [M+H] + LCMS calculated for m / z: 367.1; found: 367.0.

[0821] 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

[0822]

[0823] Dissolve (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) in DCM (700 mL) in a 3-neck 2000 mL flask. Cool the solution to -5 °C and add boron trichloride (1 M, 280 mL, 280 mmol) to the mixture while maintaining the temperature below -5 °C. Stir the mixture for 1 hour below -5 °C. Add MeOH (175 mL) to the mixture, where the temperature rises to no more than 10 °C. Concentrate the reaction mixture under reduced pressure. Purify the residue by flash chromatography on a silica gel column with a gradient of 0 - 10% DCM / MeOH to obtain (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%). C 10 H 12 ClF2N4O [M+H] + LCMS calculated value for m / z: 277.1; experimental value: 277.3.

[0824] 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

[0825]

[0826] At room temperature, sodium hydride (105 mg, 2.6 mmol, 60% dispersed 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). 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 solution (3 mL). The quenched product mixture was transferred to a separatory funnel and extracted with DCM (2 x 3 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was dissolved in EtOAc (3 mL) and washed with saturated aqueous sodium chloride solution (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 afford the title compound (250 mg, 67%). C 18 H 19 ClF2N5O3 [M+H] + LCMS calculated for m / z: 426.1; found: 426.2.

[0827] 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

[0828]

[0829] (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), tripotassium phosphate (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 with a gradient of 0 - 50% EtOAc / DCM to afford the title compound (124 mg, 48%). C 24 H 23 F3N5O4 [M+H] + LCMS calculated for m / z: 502.2; found: 502.3.

[0830] 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

[0831]

[0832] 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 afford the title compound (151 mg, 100%) which was used without further purification. C 22 H 19 F3N5O3 [M+H] +LCMS calculated value of m / z: 458.1; experimental value: 458.3.

[0833] 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)

[0834]

[0835] Add N,N-diisopropylethylamine (213 mg, 1.65 mmol) 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 DMSO (1.5 mL). Heat the reaction mixture to 45 °C and stir for 2 h. Cool the reaction mixture to room temperature. At room temperature, add sodium triacetoxyborohydride (210 mg, 0.99 mmol) to the reaction mixture. Heat the reaction mixture to 35 °C and stir for 16 h. Quench the product mixture with water and extract twice with DCM. Dry the combined organic layers over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by preparative HPLC to obtain (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%).

[0836] 11H NMR (400 MHz, CD3OD) δ 8.46 (d, J = 2.3 Hz, 1H), 8.08 (dd, J = 8.7, 2.4 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.38 – 7.29 (m, 4H), 7.10 (s, 1H), 7.06 – 6.96 (m, 2H), 6.20 (t, J = 55.7 Hz, 1H), 5.90 (s, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.47 (s, 2H), 4.44 – 4.34 (m, 2H), 4.29 (dd, J = 12.9, 6.1 Hz, 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, 6.9 Hz, 1H), 2.95 – 2.83 (m, 1H), 2.77 (ddd, J = 17.5, 4.5, 2.3 Hz, 1H), 2.48 (qd, J = 13.2, 4.7 Hz, 1H), 2.31 – 2.11 (m, 2H). C 39 H 39 F3N9O5 [M+H] + Calculated LCMS value of m / z: 770.3; Experimental value: 770.8.

[0837] 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

[0838]

[0839] Step 1: 5-Bromo-3-ethylpyridin-2-amine

[0840]

[0841] At 0 °C, 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). The reaction mixture was stirred at 0 °C for 1 h, then warmed to room temperature and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel using a gradient of 0 - 10% MeOH / DCM to afford 5-bromo-3-ethylpyridin-2-amine (1.52 g, 92%). C7H 10 BrN2 [M+H] + LCMS calculated for m / z: 201.0; found: 201.0.

[0842] Step 2: 5-Bromo-3-ethylpyridin-2-ol

[0843]

[0844] At 0 °C, sodium nitrite (2.57 g, 37.3 mmol) dissolved in water (15 mL) was added dropwise over 15 min 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 h. The product mixture was diluted with water (50 mL) and extracted with 3:1 chloroform:isopropanol solution (4 x 100 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to afford 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.

[0845] Step 3: 3-Ethyl-5-vinylpyridin-2-ol

[0846]

[0847] Charge a 40 mL scintillation vial with vinyl boronic 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). Dissolve the mixture in 1,4-dioxane (10 mL) and water (3 mL). Sparge the reaction mixture with N2 gas for 5 minutes, seal and heat to 100 °C. Stir the reaction mixture at 100 °C for 1 hour. Dilute the product mixture with MeOH (10 mL), filter and concentrate under reduced pressure. Purify the obtained residue by flash column chromatography on silica gel with a gradient of 0 - 20% MeOH / DCM to afford 3-ethyl-5-vinylpyridin-2-ol (385 mg, 96%). C9H 12 NO [M+H] + LCMS calculated for m / z: 150.1; found: 150.0.

[0848] Step 4: (2R,4S)-1-(tert-Butyl) 2-methyl 4-(benzyloxy)pyrrolidine-1,2-dicarboxylate

[0849]

[0850] At 0 °C, add sodium hydride (2.45 g, 61.2 mmol, 60% dispersion in mineral oil) to a stirred solution of (2R,4S)-1-(tert-butyl) 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (10.0 g, 40.8 mmol) in THF (100 mL). Stir the reaction mixture for 30 minutes. At 0 °C, add benzyl bromide (7.27 mL, 61.2 mmol) to the stirred reaction mixture. Warm the reaction mixture to room temperature and stir for 3 hours. Pour the product mixture into saturated aqueous ammonium chloride (200 mL) and extract with DCM (3 x 150 mL). Dry the combined organic layers over Na2SO4, filter and concentrate under reduced pressure. Purify the obtained residue by flash column chromatography on silica gel with a gradient of 0 - 50% EtOAc / hexane to afford (2R,4S)-1-(tert-butyl) 2-methyl 4-(benzyloxy)pyrrolidine-1,2-dicarboxylate (10.7 g, 78%). C 13 H 18 NO3 [M+H-C5H9O2] + LCMS calculated for m / z: 236.1; found: 236.0.

[0851] 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

[0852]

[0853] This intermediate was synthesized by a procedure similar to the procedure described in Example 40, using methyl 1-(tert-butyl) 2-[(2R,4S)-4-(benzyloxy)pyrrolidine-1,2-dicarboxylate] instead of methyl 1-(tert-butyl) 2-[(2S,4R)-4-(benzyloxy)pyrrolidine-1,2-dicarboxylate] in Step 2 of Example 40.C 17 H 16 ClF2N4O2 [M+H] + LCMS calculated value of m / z: 381.1; experimental value: 380.9.

[0854] 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

[0855]

[0856] At room temperature, 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). The reaction mixture was heated to 55 °C and stirred for 2 h. 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 h. The reaction mixture was cooled to 0 °C and quenched by slow addition of MeOH (10 mL). The quenched reaction mixture was concentrated under reduced pressure. The residue obtained 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 to the reaction mixture in sequence. The reaction mixture was heated to 70 °C and stirred for 30 h. 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 x 200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel using a gradient of 0 - 10% MeOH / DCM to afford (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%). C 17 H 18 ClF2N4O [M+H] + LCMS calculated for m / z: 367.1; found: 367.0.

[0857] 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

[0858]

[0859] At 0 °C, 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). 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 3:1 chloroform:isopropanol solution (4 x 100 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to afford (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%). C 10 H 12 ClF2N4O [M+H] + LCMS calculated for m / z: 277.1; found: 276.9.

[0860] 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

[0861]

[0862] Diisopropyl azodicarboxylate (64.0 µL, 0.33 mmol) was added to a stirred solution of polymer-bound triphenylphosphine (ca. 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 residue obtained was purified by flash column chromatography on silica gel using a gradient of 0-10% MeOH / DCM to afford (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%). C 19 H 21 ClF2N5O [M+H] + LCMS calculated for m / z: 408.1; found: 408.1.

[0863] 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

[0864]

[0865] Charge a 20 mL scintillation vial 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). Dissolve the mixture in 1,4-dioxane (1.5 mL) and water (400 μL). Sparge the reaction mixture with N2 gas for 5 minutes, seal and heat to 80 °C. Stir the reaction mixture at 80 °C for 1 hour. Transfer the product mixture to a separatory funnel containing saturated sodium bicarbonate solution (40 mL) and extract with 3:1 chloroform:isopropanol solution (3 x 30 mL). Dry the combined organic layers over MgSO4, filter and concentrate under reduced pressure. Purify the obtained residue by flash column chromatography on silica gel using a gradient of 0-10% MeOH / DCM to afford the title compound (90 mg, 95%). C 25 H 25 F3N5O2 [M+H] + LCMS calculated for m / z: 484.2; found: 484.0.

[0866] 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

[0867]

[0868] 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-ethenylpyridin-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 h. 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 3:1 chloroform:isopropanol solution (3 x 30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained 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 min. The product mixture was transferred to a separatory funnel with saturated aqueous sodium bicarbonate (30 mL). The diluted product mixture was extracted with 3:1 chloroform:isopropanol solution (3 x 30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound (70 mg, 78%). The residue obtained was used directly in the next step. C 24 H 23 F3N5O3 [M+H] + LCMS calculated for m / z: 486.2; found: 486.0.

[0869] 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)

[0870]

[0871] 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 h. 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 x 100 mm, 7.2-25.2% MeCN / water (containing 0.1% TFA), in 12 min) to afford the title compound (19.7 mg, 27%) as its TFA salt.

[0872] 11H NMR (600 MHz, DMSO) δ 10.90 (s, 1H), 9.90 (s, 1H), 8.10 (s, 1H), 7.66 (s, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.32 – 7.23 (m, 2H), 7.20 (d, J = 2.4 Hz, 1H), 7.13 (s, 1H), 6.89 – 6.83 (m, 1H), 6.27 (t, J = 55.4 Hz, 1H), 5.76 (p, J = 5.8 Hz, 1H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.34 – 4.26 (m, 3H), 4.17 (d, J = 16.9 Hz, 1H), 4.09 (dd, J = 12.8, 6.2 Hz, 1H), 3.94 – 3.76 (m, 4H), 3.26 ...

Claims

1. A compound of formula (I): （I） or a pharmaceutically acceptable salt thereof; wherein R1 is halogenated, C 1-6 alkyl or C 1-6 haloalkyl; each R2 is independently H, D or F; Each R3 is independently H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 heterocycloalkyl or C 3-6 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 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 or a 5-6-membered heteroaryl; ring A2 is a 3-7-membered cycloalkyl or a 4-7-membered heterocycloalkyl; 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); wherein the alkyl, haloalkyl, cycloalkyl, alkoxyalkyl, aryl, heteroaryl or heterocycloalkyl is optionally substituted with one or more R f groups; Each Rf is independently D, oxo, halogen, C1-C8 alkoxy, C1-C8 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)2NR 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)2R b , -C(O)NR b OR b , -S(O)2OR b , -OS(O)2OR b or -OPO(OR b )(OR b ); wherein said C1-C8 alkyl is optionally substituted with 1-6 groups selected from: D, halogen, -OH, -CN, -OR a , -SR a , -NR a R d or NR c R d ; Each R a is 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)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 is 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 is independently H, D, -C1-C 10 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OC1-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 R c and R d Together with the atoms to which both are attached, form a monocyclic or polycyclic heterocycloalkyl or monocyclic or polycyclic heterocycloalkenyl group.

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

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

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

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

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

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

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

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

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

14. The compound according to any one of the preceding claims, wherein R4 is H.

15. The compound according to any one of claims 1 to 13, wherein R4 is D.

16. The compound according to any one of claims 1 to 13, wherein R4 is C 1-6 alkyl.

17. The compound according to any one of claims 1 to 13, wherein R4 is methyl.

18. The compound according to any one of the preceding claims, wherein R5 is H.

19. The compound according to any one of the preceding claims, wherein L1 is O.

20. The compound according to any one of claims 1 to 18, wherein L1 is NR3.

21. The compound according to any one of claims 1 to 18, wherein L1 is S.

22. The compound according to any one of the preceding claims, wherein L2 is CO.

23. The compound according to any one of claims 1 to 21, wherein L2 is C(R3)2.

24. The compound according to any one of claims 1 to 21, wherein L2 is methylene.

25. The compound according to any one of the preceding claims, wherein ring A1 is a 6-membered aryl.

26. The compound according to claim 25, wherein ring A1 is phenyl.

27. The compound according to any one of claims 1 to 24, wherein ring A1 is a 5- or 6-membered heteroaryl.

28. The compound according to claim 27, wherein ring A1 is a pyridine group.

29. The compound according to any one of the preceding claims, wherein ring A2 is a 4- to 7-membered heterocycloalkyl.

30. The compound according to claim 29, wherein ring A2 is a piperidine group or a piperazine group.

31. The compound according to any one of the preceding claims, wherein X1 is CH2.

32. The compound according to any one of claims 1 to 30, wherein X1 is CO.

33. The compound according to any one of the preceding claims, wherein X2 is CH2.

34. The compound according to any one of claims 1 to 32, wherein X2 is CO.

35. The compound according to any one of the preceding claims, which is a compound of formula IIa or formula IIb: (IIa) (IIb) or a pharmaceutically acceptable salt thereof.

36. The compound according to any one of the preceding claims, which is a compound of formula IIIa or formula IIIb: (IIIa) (IIIb) or a pharmaceutically acceptable salt thereof; wherein each Z is independently N or CR6; and Each R6 is independently H, D, halogenated, -CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 3-6 cycloalkyl.

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

38. The compound according to claim 36 or claim 37, wherein at least two Zs are N.

39. The compound according to any one of claims 36 to 38, wherein at least one Z is CR6.

40. The compound according to any one of claims 36 to 39, wherein at least two Zs are CR6.

41. The compound according to any one of claims 36 to 40, wherein at least one R6 is H.

42. A compound according to any one of claims 36 to 40, wherein at least one R6 is C 1-6 alkyl.

43. The compound according to claim 42, wherein at least one R6 is methyl.

44. The compound according to any one of claims 36 to 43, which is a compound of formula IVa or formula IVb: (IVa) (IVb) or a pharmaceutically acceptable salt thereof; wherein Z1 is N or CR6.

45. The compound according to claim 44, wherein Z1 is N.

46. The compound according to claim 44, wherein Z1 is CR6.

47. The compound according to any one of claims 36 to 46, which is a compound of formula Va or formula Vb: (Va) (Vb) or a pharmaceutically acceptable salt thereof.

48. The compound according to any one of claims 36 to 47, which is a compound of formula VIa or formula VIb: (VIa) (VIb) or a pharmaceutically acceptable salt thereof.

49. The compound according to any one of claims 36 to 47, which is a compound of formula VIIa or formula VIIb: (VIIa) (VIIb) or a pharmaceutically acceptable salt thereof.

50. The compound according to claim 1, which 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-hexahydropyrrolo[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-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-(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)-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-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-(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-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-(4-(4-(((6aR,8R)-2-(3-chloro-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-hexahydropyrrolo[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-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-(4-(4-(((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)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-hexahydropyrrolo[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-hexahydropyrrolo[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-hexahydropyrrolo[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-hexahydropyrrolo[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-hexahydropyrrolo[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-hexahydropyrrolo[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-hexahydropyrrolo[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-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-(4-(4-(((6aR,8R)-2-(2-hydroxy-3-methylphenyl)-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-(4-(4-(((6aR,8R)-2-(3-chloro-2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[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-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-hexahydropyrrolo[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-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-((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)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-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-((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; (S)-3-(6-(1-((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)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-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-((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)-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-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)-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; 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; 3-(6-(4-((6-(((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)(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)sulfanyl)-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. The compound according to claim 1, wherein it 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)sulfanyl)-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-hexahydropyrrolo[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. A compound according to any one of the preceding claims, in the form of a pharmaceutically acceptable salt.

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

55. The method according to claim 54, wherein the cancer is a SMARCA4-deficient cancer.

56. The method according to claim 54 or claim 55, wherein the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and renal cell carcinoma, bladder cancer, bowel cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer; leukemia; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, rhabdomyosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineocytoma, meningioma, meningeal sarcoma, neurofibroma and schwannoma; bowel 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. The method according to 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, pre-B ALL, pre-B lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL and Philadelphia chromosome-positive CML.

58. The method according to claim 56, wherein the lung cancer is SMARCA4-deficient non-small cell lung cancer.

59. A method of 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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