BRM targeting compounds and related methods of use

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 036,811, filed June 9, 2020, which is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure provides bifunctional compounds comprising a target protein binding portion and an E3 ubiquitin ligase binding portion, and related methods of use. The bifunctional compounds can be used as modulators of targeted ubiquitination, particularly a matrix-associated actin-dependent regulator of the switch / sucrose non-fermentable (SWI / SNF)-related chromatin subfamily A member 2 (SMARCA2) (i.e., BRAHMA or BRM), which is degraded and / or otherwise inhibited by the bifunctional compounds according to the present disclosure. Background Art

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

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

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

[0007] SMARCA2 and SMARCA4 have a high degree of homology (up to 75%). SMARCA4 is frequently mutated (i.e., deleted or inactivated) in primary tumors, particularly in lung cancer (12%), melanoma, liver cancer, and pancreatic cancer. SMARCA2 is one of the most important essential genes in SMARCA4-mutant (deleted) cancer cell lines. This is because SMARCA4-deficient cancer cells are completely dependent on SMARCA2 ATPase activity to achieve their chromatin remodeling activity to achieve cellular functions such as cell proliferation, survival, and growth. Therefore, targeting SMARCA2 may be a promising treatment approach for SMARCA4-associated or defective cancers (genetic synthetic lethality).

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

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

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

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

[0012] PTMULM(I)

[0013] or a pharmaceutically acceptable salt or solvate thereof,

[0014] in

[0015] PTM is a moiety of formula IA:

[0016]

[0017] in

[0018] R 1 is a covalent bond or a chemical moiety connecting the PTM and the ULM;

[0019] * is the attachment point to the ULM;

[0020] n = 0-3;

[0021] W is optionally substituted -CH2-, -C(O)-, -S(O)-, or -S(O)2-, wherein when n=2 or 3, only one W can be -C(O)-, -S(O)-, or -S(O)2-;

[0022] R c1and R d1 are independently H, D, halo, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-4 alkoxy;

[0023] R e3 H, -C(O)R f OR-P(O)(OR g )2; where R f and R g Independently H, C 1-4 Alkyl, C 1-4 Substituted alkyl, C 3-8 Cycloalkyl, C 3-8 Substituted cycloalkyl, C 3-8 Heterocycloalkyl or C 3-8 substituted heterocycloalkyl;

[0024] Z and Y are each independently N; CR h , where R h =H or absent; or, if R 1 Attached to Z, then Z is C and Y is N or CR h , where R h is H; or if R 1 Attached to Y, then Y is C and Z is N or CR h , where R h is H;

[0025] B is an optionally substituted 5-7 membered cycloalkyl ring, an optionally substituted 5-7 membered heteroaryl ring, or an optionally substituted 5-7 membered heterocyclic ring, wherein Ring B is fused to Ring C through Y and Z; and

[0026] ULM is a small molecule E3 ubiquitin ligase binding moiety that binds to the Von Hippel-Lindau E3 ubiquitin ligase. DETAILED DESCRIPTION

[0027] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terms used in the specification are for describing particular embodiments only and are not intended to limit the disclosure.

[0028] Where a numerical range is provided, it is understood that unless the context clearly dictates otherwise, each intervening value, to the tenth of the unit of the lower limit (such as in the case of a group containing a certain number of carbon atoms, in which case each number of carbon atoms falling within the range is provided), and any other stated or intervening value in the stated range are encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where a stated range includes one or both limits, ranges excluding either of those included limits are also encompassed within the disclosure.

[0029] The following terms are used to describe the present disclosure. In the event that a term is not specifically defined herein, the term is given the art-recognized meaning by one of ordinary skill in the art and is applied to the context in which it is used when describing the present disclosure.

[0030] Unless the context clearly dictates otherwise, the articles "a" and "an" as used herein and in the appended claims are used herein to refer to one or more than one (e.g., at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.

[0031] The terms "co-administration" and "co-administering" or "combination therapy" refer to both simultaneous administration (administering two or more therapeutic agents at the same time) and time-varying administration (administering one or more therapeutic agents at a time different from the time of administration of one or more additional therapeutic agents), as long as the therapeutic agents are present in the patient's body at the same time, preferably in effective amounts, to some extent. In certain preferred aspects, one or more compounds of the invention described herein are co-administered in combination with at least one additional biologically active agent, particularly including anticancer agents. In particularly preferred aspects, co-administration of the compounds results in synergistic activity and / or treatment, including anticancer activity.

[0032] Unless otherwise indicated, as used herein, the term "compound" refers to any specific chemical compound disclosed herein, and includes, in the context of the present invention, tautomers, regioisomers, geometric isomers, and, where applicable, stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers), and pharmaceutically acceptable salts and derivatives thereof, including, where applicable, prodrugs and / or deuterated forms thereof. Deuterated small molecules are contemplated as those in which one or more hydrogen atoms contained in the drug molecule have been replaced by deuterium.

[0033] In its use in this context, the term compound generally refers to a single compound, but may also include other compounds, such as stereoisomers, regioisomers and / or optical isomers (including racemic mixtures) as well as specific enantiomers or enantiomerically enriched mixtures of the disclosed compounds. The term also refers to prodrug forms of the compounds in this context, which 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 are described, inter alia, in connection therewith. It will be understood by those of ordinary skill in the art that the molecules described herein are stable compounds as generally described below.

[0034] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, targeting them for degradation. For example, E3 ubiquitin ligase proteins, alone or in combination with E2 ubiquitin conjugating enzymes, cause ubiquitin to attach to a lysine on a target protein and subsequently target that specific protein substrate for degradation by the proteasome. Thus, E3 ubiquitin ligases, alone or in complex with E2 ubiquitin conjugating enzymes, are responsible for the transfer of ubiquitin to target proteins. Generally speaking, ubiquitin ligases participate in polyubiquitination, allowing a second ubiquitin to attach to a first ubiquitin; a third ubiquitin to attach to a second ubiquitin, and so on. Polyubiquitination marks proteins for proteasomal degradation. However, there are some ubiquitination events that are limited to monoubiquitination, in which only a single ubiquitin is added to a substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted for degradation by the proteasome, but instead may alter their cellular location or function, for example, by binding to other proteins with domains capable of binding ubiquitin. Further complicating the issue, different lysines on ubiquitin can be targeted by E3s to generate chains. The most common lysine is Lys48 in the ubiquitin chain. This is the lysine used to make polyubiquitin, which is recognized by the proteasome.

[0035] As used herein, the term "alkyl," by itself or as part of another substituent, refers to a straight or branched chain hydrocarbon radical having up to twelve carbon atoms, unless otherwise indicated. In some embodiments, the number of carbon atoms specified (i.e., C 1- C8 means one to eight carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Alkyl groups may be optionally substituted as provided herein. In some embodiments, the alkyl group is C 1- C6 alkyl; in some embodiments, it is C 1- C4 alkyl.

[0036] When a range of carbon atoms is used herein, for example, all ranges of C1-C6 as well as individual carbon atom numbers are encompassed. For example, "C1-C3" includes C1-C3, C1-C2, C2-C3, C1, C2, and C3.

[0037] The term "optionally substituted" used in conjunction with a substituent as defined herein means that the substituent may be, but is not required to be, substituted with one or more suitable functional groups or other substituents provided herein. For example, a substituent may be optionally substituted with one or more of the following groups: halo, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo (C 1-6 ) alkyl, C 1-6 Alkoxy, halogenated (C 1-6 Alkoxy), C 1-6 Alkylthio, C 1-6 Alkylamino, NH2, NH(C 1-6 alkyl), N(C 1-6 Alkyl)2, NH(C 1-6 Alkoxy), N(C 1-6 Alkoxy)2, -C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6 alkyl)2, -C(O)NH2, -C(O)C 1-6 Alkyl, -C(O)2C 1-6 Alkyl, -NHCO(C 1-6 Alkyl), -N(C 1-6 alkyl)CO(C 1-6 alkyl), -S(O)C 1-6 Alkyl, -S(O)2C 1-6 alkyl, oxo, 6-12 membered aryl, benzyl, pyridyl, pyrazolyl, thiazolyl, isothiazolyl or other 5 to 12 membered heteroaryl groups. In some embodiments, each of the above optional substituents is itself optionally substituted with one or two groups.

[0038] As used herein, the term "cycloalkyl" refers to a 3-12 membered cycloalkyl group, and includes bridged rings and spiro rings (e.g., adamantyl). Cycloalkyl groups can be fully saturated or partially unsaturated. The term "cycloalkyl" also includes polycondensed ring systems (e.g., ring systems comprising 2, 3, or 4 rings), wherein a single cycloalkyl ring (as defined above) can be condensed with one or more groups selected from heterocycles, carbocycles, aryls, or heteroaryls to form polycondensed ring systems. Such polycondensed ring systems can optionally be substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocycle or heterocyclic moieties of the polycondensed rings. When valence requirements allow, the rings of the polycondensed ring systems can be connected to each other via fused bonds, spiro bonds, and bridge bonds. It should be understood that the individual rings of the polycondensed ring systems can be connected in any order relative to each other. It should also be understood that the attachment point of the polycondensed ring systems (as defined above for cycloalkyl) can be at any position of the cycloalkyl ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclohexyl, cycloheptyl, cyclooctyl, indenyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[4.1.0]heptyl, spiro[3.3]heptyl, and spiro[3.4]octyl. In some embodiments, the cycloalkyl group is a 3-7 membered cycloalkyl.

[0039] As used herein, the term "alkenyl" refers to a C 2- C 12 In some embodiments, the alkenyl group is optionally substituted. In some embodiments, the alkenyl group is C 2- C6 alkenyl.

[0040] As used herein, the term "alkynyl" refers to a C 2- C 12 In some embodiments, the alkenyl group is optionally substituted. In some embodiments, the alkynyl group is C 2- C6 alkynyl.

[0041] The terms "alkoxy," "alkylamino," and "alkylthio" are used in their conventional sense and refer to those alkyl groups that are attached to the remainder of the molecule through an oxygen atom ("oxy"), an amino group ("amino"), or a thiol group. The term "alkylamino" includes mono- and di-alkylamino groups, the alkyl portions of which may be the same or different.

[0042]

[0046] The terms "halo" or "halogen," by themselves or as part of another substituent, refer to a fluorine, chlorine, bromine, or iodine atom.

[0043] The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms have been replaced by heteroatoms selected from S, O, P, and N. Exemplary heteroalkyl groups include alkyl ethers, secondary and tertiary alkylamines, alkylamides, alkyl sulfides, and the like. This group can be a terminal group or a bridging group. As used herein, when used in the context of a bridging group, reference to a normal chain refers to a direct chain connecting the atoms at the two terminal positions of the bridging group.

[0044] As used herein, the term "aryl" refers to a single all-carbon aromatic ring or a plurality of condensed all-carbon ring systems, wherein at least one ring is aromatic. For example, in certain embodiments, the aryl group has 6 to 12 carbon atoms. Aryl includes phenyl. Aryl also includes a polycondensed ring system (for example, a ring system comprising 2, 3 or 4 rings) with about 9 to 12 carbon atoms, wherein at least one ring is aromatic, and wherein other rings may be aromatic or non-aromatic. Such polycondensed ring systems are optionally substituted with one or more (for example, 1, 2 or 3) oxo groups on any carbocyclic ring portion of the polycondensed ring system. When valence requirements allow, the rings of the polycondensed ring system can be connected to each other via fused bonds, spiro bonds and bridge bonds. It should be understood that the attachment point of the polycondensed ring system as defined above can be at any position of the aromatic ring. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, etc.

[0045] As used herein, the term "heteroaryl" refers to a single aromatic ring having at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen, and sulfur; "heteroaryl" also includes polycondensed ring systems having at least one such aromatic ring, which are further described below. Thus, "heteroaryl" includes a single aromatic ring having about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms may also exist in oxidized form, provided that the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furanyl. "Heteroaryl" also includes polycondensed ring systems (e.g., ring systems containing 2, 3, or 4 rings), wherein a heteroaryl group as defined above is condensed with one or more rings selected from heteroaryl (to form, for example, naphthyridinyl, such as 1,8-naphthyridinyl), heterocycle (to form, for example, 1,2,3,4-tetrahydronaphthyridinyl, such as 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (to form, for example, 5,6,7,8-tetrahydroquinolinyl), and aryl (to form, for example, indazolyl) to form a polycondensed ring system. Thus, the heteroaryl group (single aromatic ring or polycondensed ring system) has about 1-20 carbon atoms and about 1-6 heteroatoms within the heteroaryl ring. The heteroaryl group (single aromatic ring or polycondensed ring system) can also have about 5 to 12 or about 5 to 10 members within the heteroaryl ring. Polycondensed ring systems can be optionally substituted with one or more (for example, 1,2,3 or 4) oxo groups on the carbocyclic ring or heterocyclic ring moiety of the condensed ring. When valence requirements allow, the rings of polycondensed ring systems can be connected to each other via fused bonds, spiro bonds and bridge bonds. It should be understood that the individual rings of polycondensed ring systems can be connected in any order relative to each other. It should also be understood that the attachment point of polycondensed ring systems (as defined above for heteroaryl) can be at any position of the heteroaryl ring. It should also be understood that the attachment point of heteroaryl or heteroaryl polycondensed ring systems can be at any suitable atom of the heteroaryl ring, including carbon atoms and heteroatoms (for example, nitrogen). Exemplary heteroaryl groups include, but are not limited to, pyridinyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinylbenzofuranyl, benzimidazolyl, thianaphthyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indole, and 3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazole. In one embodiment, the term "heteroaryl" refers to a single aromatic ring containing at least one heteroatom. For example, the term includes 5- and 6-membered monocyclic aromatic rings containing one or more heteroatoms.Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thiazole, pyrimidine, oxazole, and thiadiazole.

[0046] As used herein, the term "heterocyclyl" or "heterocycle" refers to a single saturated or partially unsaturated ring having at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; the term also includes a polycondensed ring system with at least one such saturated or partially unsaturated ring, which is further described below. Therefore, the term includes a single saturated or partially unsaturated ring (e.g., 3, 4, 5, 6 or 7-membered ring) having about 1 to 6 carbon atoms and about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The ring may be substituted by one or more (e.g., 1, 2 or 3) oxo groups, and sulfur and nitrogen atoms may also exist in their oxidized forms. Exemplary heterocycles include, but are not limited to, azetidinyl, tetrahydrofuranyl and piperidinyl. The term "heterocycle" also includes polycondensed ring systems (e.g., ring systems comprising 2, 3, or 4 rings), wherein a single heterocycle (as defined above) may be condensed with one or more groups selected from heterocycles (to form, for example, 1,8-decahydronaphthyridinyl), carbocycles (to form, for example, decahydroquinolinyl), and aryl groups to form a polycondensed ring system. Thus, the heterocycle (single saturated or single partially unsaturated ring or polycondensed ring system) has about 2-20 carbon atoms and 1-6 heteroatoms within the heterocycle. Such polycondensed ring systems may optionally be substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocycle or heterocycle portion of the polycondensed ring. When valence requirements permit, the rings of the polycondensed ring system may be connected to each other via fused bonds, spiro bonds, and bridge bonds. It should be understood that the individual rings of the polycondensed ring system may be connected in any order relative to each other. Thus, a heterocycle (single saturated or single partially unsaturated ring or a polycondensed ring system) has about 3-20 atoms within the heterocycle system, including about 1-6 heteroatoms. It is also understood that the point of attachment of a polycondensed ring system (as defined above for heterocyclyl) can be at any position of the heterocycle. It is also understood that the point of attachment of a heterocycle or heterocyclic polycondensed ring system can be at any suitable atom of the heterocycle, including carbon atoms and heteroatoms (e.g., nitrogen). In one embodiment, the term heterocycle includes C 2-20 In one embodiment, the term heterocycle includes C 2-7 In one embodiment, the term heterocycle includes C 2-5 In one embodiment, the term heterocycle includes C 2-4Heterocycles. Exemplary heterocycles include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolinyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, spiro[cyclopropane-1,1′-isoindolinyl]-3′-one, isoindolinyl-1-one, 2-oxa-6-azaspiro[3.3]heptanyl, imidazolidin-2-one N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolinone, hydantoin, dioxolane, phthalimide, 1,4-dioxane, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, pyran, 3-pyrroline, thiopyran, pyrone, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane and pyrrolidin-2-one. In one embodiment, the term "heterocycle" refers to a monocyclic, saturated or partially unsaturated 3-8 membered ring having at least one heteroatom. For example, the term includes monocyclic, saturated or partially unsaturated 4, 5, 6 or 7 membered rings having at least one heteroatom. Non-limiting examples of heterocycles include aziridine, azetidine, pyrrolidine, piperidine, piperidine, piperazine, oxirane, morpholine and thiomorpholine. As used herein, the term "9 or 10 membered heterobicyclic ring" refers to a partially unsaturated or aromatic fused bicyclic ring system having at least one heteroatom. For example, the term 9 or 10 membered heterobicyclic ring includes a bicyclic ring system having a benzo ring fused to a 5 or 6 membered saturated, partially unsaturated or aromatic ring containing one or more heteroatoms.

[0047] As used herein, the term "heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si). Where applicable, the nitrogen and sulfur may be in oxidized form.

[0048] As used herein, the term "chiral" refers to molecules that have the property that their mirror image partner is non-superimposable, while the term "achiral" refers to molecules that are superimposable on their mirror image partner.

[0049] As used herein, the term "stereoisomers" refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space, eg enantiomers, diastereomers, tautomers.

[0050] The term "patient" or "subject" is used throughout this specification to describe an animal, preferably a human or domesticated animal, to whom treatment, including prophylactic treatment, using a composition according to the present disclosure is provided. For treatment of those infections, disorders, or disease states that are specific to a particular animal, such as a human patient, the term patient refers to the specific animal, including domesticated animals (such as dogs or cats) or farm animals (such as horses, cattle, sheep, etc.). Generally speaking, in this disclosure, the term patient refers to a human patient unless otherwise indicated or implied by the context in which the term is used.

[0051] The term "effective" is used to describe an amount of a compound, composition, or component that achieves the intended result when used in the context of its intended use. The term effective includes all other effective amount or effective concentration terms otherwise described or used in this application.

[0052] "Pharmaceutically acceptable" means a drug that is approved or recognized by a regulatory agency of a federal or state government or its counterpart in a country outside the United States, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals (e.g., humans).

[0053] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure that are pharmaceutically acceptable and have the desired pharmacological activity of the parent compound. Specifically, such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, ... 2-hydroxybenzoyl)benzoic acid, -toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal 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 also include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and when the compound contains a basic functional group, salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate, etc.

[0054] A "pharmaceutically acceptable excipient" refers to a non-toxic, biologically tolerable, and otherwise biologically suitable substance for administration to a subject, such as an inert substance, which is added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of the pharmaceutical agent and is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0055] "Solvate" means a physical association of a compound of Formula I with one or more solvent molecules.

[0056] In one embodiment, "treating" or "treatment" of any disease or disorder refers to ameliorating the disease or disorder (e.g., preventing or reducing the development of at least one of the disease or its clinical symptoms). In another embodiment, "treating" refers to improving at least one physical parameter that the subject may not be able to discern. In yet another embodiment, "treating" refers to regulating the disease or condition physically (e.g., stabilizing an indiscernible symptom), physiologically (e.g., stabilizing a physical parameter), or both. In yet another embodiment, "treating" refers to delaying the onset of a disease or condition.

[0057] In one aspect, the present disclosure relates to compounds of formula (I):

[0058] PTM-ULM(I)

[0059] or a pharmaceutically acceptable salt or solvate thereof, wherein PTM is a moiety of Formula IA:

[0060]

[0061] in

[0062] R 1 is a covalent bond or a chemical moiety connecting the PTM and the ULM;

[0063] * is the attachment point to the ULM;

[0064] n = 0-3;

[0065] each W is independently optionally substituted -CH2-, -C(O)-, -S(O)-, or -S(O)2-, wherein when n=2 or 3, only one W can be -C(O)-, -S(O)-, or -S(O)2-;

[0066] R c1 and R d1 are independently H, D, halo, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-4 alkoxy;

[0067] R e3 H, -C(O)R f OR-P(O)(OR g )2; where R f and R g Independently H, C 1-4 Alkyl, C 1-4 Substituted alkyl, C 3-8 Cycloalkyl, C 3-8 Substituted cycloalkyl, C 3-8 Heterocycloalkyl or C 3-8 substituted heterocycloalkyl;

[0068] Z and Y are each independently N or CR h , where R h =H or not present, or if R 1 Attached to Z, then Z is C and Y is N or CR h , where R h is H; or if R 1 Attached to Y, then Y is C and Z is N or CR h , where R h is H;

[0069] B is an optionally substituted 5-7 membered cycloalkyl ring, an optionally substituted 5-7 membered heteroaryl ring, or an optionally substituted 5-7 membered heterocyclic ring, wherein ring B is fused to ring C through Y and Z; and ULM is a small molecule E3 ubiquitin ligase binding moiety that binds von Hippel-Lindau E3 ubiquitin ligase.

[0070] In some aspects, the compound of Formula I includes a protein targeting moiety (PTM). In some aspects, the PTM in the compound of Formula I is a moiety of Formula IA

[0071]

[0072] According to the present disclosure, B is a ring fused to ring "C" via Y and Z.

[0073] In some aspects, B in Formula IA is an optionally substituted 5-7 membered cycloalkyl ring, an optionally substituted 5-7 membered heteroaryl ring, or an optionally substituted 5-7 membered heterocyclic ring.

[0074] In some embodiments, B in Formula IA is an optionally substituted 5-7 membered cycloalkyl ring.

[0075] In some embodiments, B in Formula IA is an optionally substituted 5-7 membered cycloalkyl ring, wherein the optional substituent is hydroxy, halo, alkoxy, alkyl, haloalkyl, amino, alkylamino, or cyano.

[0076] In some embodiments, B in Formula IA is an optionally substituted 5-7 membered heteroaryl ring.

[0077] In some embodiments, B in Formula IA is an optionally substituted 5-7 membered heteroaryl ring, wherein the optional substituent is hydroxy, halo, alkoxy, alkyl, haloalkyl, amino, alkylamino, or cyano.

[0078] In other embodiments, B in Formula IA is an optionally substituted 5-7 membered heterocycle.

[0079] In some embodiments, B in Formula IA is an optionally substituted 5-7 membered heterocycle, wherein the optional substituent is hydroxy, halo, alkoxy, alkyl, haloalkyl, amino, alkylamino, or cyano.

[0080] In some aspects, n in Formula IA is 0-3. In some embodiments, n = 0. In other embodiments, n = 1. In other embodiments, n = 2. In other embodiments, n = 3.

[0081] In some aspects, each W in Formula IA is independently optionally substituted -CH2-, -C(O)-, -S(O)-, or -S(O)2-, wherein when n=2 or 3, only one W can be -C(O)-, -S(O)-, or -S(O)2-.

[0082] In some embodiments, W in Formula IA is optionally substituted -CH2-. In other embodiments, W in Formula IA is -CH2-.

[0083] In some embodiments, W in Formula IA is optionally substituted -CH2-, wherein the optional substituent is an alkyl group, such as, for example, methyl (-CH3), ethyl, propyl, and the like.

[0084] In other embodiments, W in Formula IA is -C(CH3)H-.

[0085] In some embodiments, W in Formula IA is -C(O)-.

[0086] In some embodiments, W in Formula IA is -S(O)-.

[0087] In some embodiments, W in Formula IA is optionally substituted -S(O)2-.

[0088] In embodiments of the present disclosure where n is 2 or 3, then only one W can be -C(O)-, -S(O)-, or -S(O)2-.

[0089] In some aspects, R in Formula IA c1 and R d1are independently H, D, halo, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-4 Alkoxy.

[0090] In some embodiments, R c1 For H.

[0091] In some embodiments, R c1 It is D.

[0092] In some embodiments, R c1 is a halo group, such as -F, -Cl, -Br or -I.

[0093] In some embodiments, R c1 C 1-3 Alkyl, such as -C1 alkyl, -C2 alkyl, -C3 alkyl, -CH3, -CH2CH3 and the like.

[0094] In some embodiments, R c1 C 1-3 Haloalkyl, such as -C1 haloalkyl, -C2 haloalkyl, -C3 haloalkyl, -CF3, -CH2CF3 and the like.

[0095] In some embodiments, R c1 C 1-4 Alkoxy, such as -C1 alkoxy, -C2 alkoxy, -C3 alkoxy, -C4 alkoxy, -OCH3, -OCH2CH3 and the like.

[0096] In some embodiments, R d1 For H.

[0097] In some embodiments, R d1 It is D.

[0098] In some embodiments, R d1 is a halo group, such as -F, -Cl, -Br or -I.

[0099] In some embodiments, R d1 C 1-3 Alkyl, such as -C1 alkyl, -C2 alkyl, -C3 alkyl, -CH3, -CH2CH3 and the like.

[0100] In some embodiments, R d1 C 1-3 Haloalkyl, such as -C1 haloalkyl, -C2 haloalkyl, -C3 haloalkyl, -CF3, -CH2CF3 and the like.

[0101] In some embodiments, R d1C 1-4 Alkoxy, such as -C1 alkoxy, -C2 alkoxy, -C3 alkoxy, -C4 alkoxy, -OCH3, -OCH2CH3 and the like.

[0102] In some aspects, R in Formula IA e3 H, -C(O)R f OR-P(O)(OR g )2; where R f and R g Independently H, C 1-4 Alkyl, C 1-4 Substituted alkyl, C 3-8 Cycloalkyl, C 3-8 Substituted cycloalkyl, C 3-8 Heterocycloalkyl or C 3-8 Substituted heterocycloalkyl.

[0103] In some embodiments, R e3 For H.

[0104] In other embodiments, R e3 -C(O)R f , where R f H, C 1-4 Alkyl, C 1-4 Substituted alkyl, C 3-8 Cycloalkyl, C 3-8 Substituted cycloalkyl, C 3-8 Heterocycloalkyl or C 3-8 Substituted heterocycloalkyl.

[0105] In other embodiments, R e3 -C(O)R f , where R f is H. In other embodiments, R e3 -C(O)R f , where R f C 1-4 Alkyl, such as -C1 alkyl, -C2 alkyl, -C3 alkyl, -C4 alkyl, -CH3, -CH2CH3 and the like.

[0106] In other embodiments, R e3 -C(O)R f , where R f C 1-4 Substituted alkyl groups, such as -C1 substituted alkyl groups, -C2 substituted alkyl groups, -C3 substituted alkyl groups and -C4 substituted alkyl groups.

[0107] In other embodiments, R e3 -C(O)R f, where R f C 3-8 Cycloalkyl groups, such as C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, C7 cycloalkyl and C8 cycloalkyl.

[0108] In other embodiments, R e3 -C(O)R f , where R f C 3-8 Substituted cycloalkyl groups, such as C3 substituted cycloalkyl groups, C4 substituted cycloalkyl groups, C5 substituted cycloalkyl groups, C6 substituted cycloalkyl groups, C7 substituted cycloalkyl groups and C8 substituted cycloalkyl groups.

[0109] In other embodiments, R e3 -C(O)R f , where R f C 3-8 Heterocycloalkyl groups, such as C3 heterocycloalkyl groups, C4 heterocycloalkyl groups, C5 heterocycloalkyl groups, C6 heterocycloalkyl groups, C7 heterocycloalkyl groups and C8 heterocycloalkyl groups.

[0110] In other embodiments, R e3 -C(O)R f , where R f C 3-8 Substituted heterocycloalkyl groups, such as C3 substituted heterocycloalkyl groups, C4 substituted heterocycloalkyl groups, C5 substituted heterocycloalkyl groups, C6 substituted heterocycloalkyl groups, C7 substituted heterocycloalkyl groups and C8 substituted heterocycloalkyl groups.

[0111] In other embodiments, R e3 -P(O)(OR g )2; where each R g Independently H, C 1-4 Alkyl, C 1-4 Substituted alkyl, C 3-8 Cycloalkyl, C 3-8 Substituted cycloalkyl, C 3-8 Heterocycloalkyl or C 3-8 Substituted heterocycloalkyl.

[0112] In other embodiments, R e3 -P(O)(OR g )2; where each R g For H.

[0113] In other embodiments, R e3 -P(O)(OR g )2; where each R g C 1-4Alkyl, such as -C1 alkyl, -C2 alkyl, -C3 alkyl, -C4 alkyl, -CH3, -CH2CH3 and the like.

[0114] In other embodiments, R e3 -P(O)(OR g )2; one of the R g is H and the other R g C 1-4 Alkyl, such as -C1 alkyl, -C2 alkyl, -C3 alkyl, -C4 alkyl, -CH3, -CH2CH3 and the like.

[0115] In other embodiments, R e3 -P(O)(OR g )2; at least one R g C 1-4 Substituted alkyl groups, such as -C1 substituted alkyl groups, -C2 substituted alkyl groups, -C3 substituted alkyl groups and -C4 substituted alkyl groups.

[0116] In other embodiments, R e3 -P(O)(OR g )2; at least one R g C 3-8 Cycloalkyl groups, such as C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, C7 cycloalkyl and C8 cycloalkyl.

[0117] In other embodiments, R e3 -P(O)(OR g )2; at least one R g C 3-8 Substituted cycloalkyl groups, such as C3 substituted cycloalkyl groups, C4 substituted cycloalkyl groups, C5 substituted cycloalkyl groups, C6 substituted cycloalkyl groups, C7 substituted cycloalkyl groups and C8 substituted cycloalkyl groups.

[0118] In other embodiments, R e3 -P(O)(OR g )2; at least one R g C 3-8 Heterocycloalkyl groups, such as C3 heterocycloalkyl groups, C4 heterocycloalkyl groups, C5 heterocycloalkyl groups, C6 heterocycloalkyl groups, C7 heterocycloalkyl groups and C8 heterocycloalkyl groups.

[0119] In other embodiments, R e3 -P(O)(OR g )2; at least one R g C 3-8Substituted heterocycloalkyl groups, such as C3 substituted heterocycloalkyl groups, C4 substituted heterocycloalkyl groups, C5 substituted heterocycloalkyl groups, C6 substituted heterocycloalkyl groups, C7 substituted heterocycloalkyl groups and C8 substituted heterocycloalkyl groups.

[0120] In some aspects, Z and Y in Formula IA are each independently N or CR h , where R h =H or may be absent when n=1-3, so that a double bond is formed between Z and Y, or if R 1 Attached to Z, then Z is C and Y is N or CR h , where R h is H; or if R 1 Attached to Y, then Y is C and Z is N or CR h , where R h is H. Examples of these embodiments include:

[0121]

[0122] In some embodiments, Z is N.

[0123] In other embodiments, Z is CR h , where R h =H.

[0124] In other embodiments, Z is CR h , where R h = does not exist, and Z is bound to Y via a double bond.

[0125] In some embodiments, Z is C and is attached to R 1 .

[0126] In some embodiments, Y is N.

[0127] In other embodiments, Y is CR h , where R h =H.

[0128] In other embodiments, Y is CR h , where R h = does not exist, and Y is bound to Z via a double bond.

[0129] In some embodiments, Y is C and is attached to R 1 .

[0130] In some embodiments, the PTM is a moiety of Formula IA, where * is the point of attachment to the ULM.

[0131] In some aspects, R in Formula IA 1It is a covalent bond or a chemical moiety that connects the PTM and the ULM.

[0132] In some embodiments, R in Formula IA 1 It is a covalent bond.

[0133] In other embodiments, R in Formula IA 1 It is the chemical part that connects PTM and ULM.

[0134] Chemical moieties for linking PTM and ULM moieties are known in the art. These moieties are sometimes referred to in the art as "linkers." In some embodiments, R 1 are chemical moieties known in the art for linking PTMs and ULMs.

[0135] In some embodiments, R in Formula IA 1 is a chemical moiety for linking a PTM and a ULM as described in U.S. Patent Application Publication No. 2019 / 0300521, the entire contents of which are incorporated herein by reference.

[0136] In other embodiments, R in Formula IA 1 is a chemical moiety for linking a PTM and a ULM as described in U.S. Patent Application Publication No. 2019 / 0255066, the entire contents of which are incorporated herein by reference.

[0137] In other embodiments, R in Formula IA 1 is a chemical moiety for linking a PTM and a ULM as described in WO 2019 / 084030, the entire contents of which are incorporated herein by reference.

[0138] In other embodiments, R in Formula IA 1 is a chemical moiety for linking a PTM and a ULM as described in WO 2019 / 084026, the entire contents of which are incorporated herein by reference.

[0139] In some embodiments, R in Formula IA 1 is a chemical structural unit represented by the following formula:

[0140] -(A) q -,

[0141] in:

[0142] q is an integer from 1 to 14;

[0143] Each A is independently selected from the group consisting of: CR 1a R 1b 、O、S、SO、SO2、NR 1c、SO2NR 1c ,SONR 1c 、SO(=NR 1c ), SO(=NR 1c )NR 1d 、CONR 1c NR 1c CONR 1d NR 1c C(O)O、NR 1c SO2NR 1d , CO, CR 1a =CR 1b 、C≡C、SiR 1a R 1b 、P(O)R 1a 、P(O)OR 1a 、(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 O(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 S(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 NR(CR 1a R 1b ) 1-4 NR 1c C(=NCN)NR 1d NR 1c C(=NCN),NR 1c C(=CNO2)NR 1d , optionally 0-6 R 1a and / or R 1b 3-11 membered cycloalkyl substituted with 0-6 R 1a and / or R 1b 3-11 membered heterocyclic group substituted by a group, optionally substituted by 0-6 R 1a and / or R 1b The aryl group substituted by the group, optionally substituted by 0-6 R 1a and / or R 1b a group-substituted heteroaryl group,

[0144] And R 1a 、R 1b 、R 1c、R 1d and R 1e Each is independently -H, D, -halo, -C1-C8 alkyl, -C1-C6 haloalkyl, -O-C1-C8 alkyl, -S-C1-C8 alkyl, -NHC1-C8 alkyl, -N(C1-C8 alkyl)2, 3-11 membered cycloalkyl, aryl, heteroaryl, 3-11 membered heterocyclyl, -O-(3-11 membered cycloalkyl), -S-(3-11 membered cycloalkyl), NH-(3-11 membered cycloalkyl), N(3-11 membered cycloalkyl)2, N-(3-11 membered cycloalkyl)(C1-C8 alkyl), -OH, -NH 2, -SH, -SO2C1-C8 alkyl, SO(NH)C1-C8 alkyl, P(O)(OC1-C8 alkyl)(C1-C8 alkyl), -P(O)(OC1-C8 alkyl)2, -C≡C-C1-C8 alkyl, -C≡CH, -CH=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=C(C1-C8 alkyl)2, -Si(OH)3, -Si(C1-C8 alkyl)3, -Si(OH)(C1-C 8 alkyl)2, -C(O)C1-C8 alkyl, -CO2H, -CN, -CF3, -CHF2, -CH2F, -NO2, -SF5, -SO2NHC1-C8 alkyl, -SO2N(C1-C8 alkyl)2, -SO(NH)NHC1-C8 alkyl, -SO(NH)N(C1-C8 alkyl)2, -SONHC1-C8 alkyl, -SON(C1-C8 alkyl)2, -CONHC1-C8 alkyl, -CON(C1-C8 alkyl)2, -N(C1-C8 alkyl)CO NH(C1-C8 alkyl), -N(C1-C8 alkyl)CON(C1-C8 alkyl)2, -NHCONH(C1-C8 alkyl), -NHCON(C1-C8 alkyl)2, -NHCONH2, -N(C1-C8 alkyl)SO2NH(C1-C8 alkyl), -N(C1-C8 alkyl)SO2N(C1-C8 alkyl)2, -NHSO2NH(C1-C8 alkyl), -NHSO2N(C1-C8 alkyl)2, or -NHSO2NH2; or where the context permits, R 1a or R 1b connected to other groups, or to each other, to form a group optionally with 0-4 R 1e The cycloalkyl and / or heterocyclyl moieties are substituted by radicals.

[0145] In these embodiments, q represents the number of attached A groups. For example, when q=1, -(A) q - is -A1-; when q=2, -(A) q- is -A1-A2-; when q=3, -(A) q - is -A1-A2-A3-; when q=4, -(A) q - is -A1-A2-A3-A4-; when q=5, -(A) q - is -A1-A2-A3-A4-A5-; when q=6, -(A) q - is -A1-A2-A3-A4-A5-A6-; when q=7, -(A) q - is -A1-A2-A3-A4-A5-A6-A7-; when q=8, -(A) q - is -A1-A2-A3-A4-A5-A6-A7-A8-; when q=9, -(A) q - is -A1-A2-A3-A4-A5-A6-A7-A8-A9-; when q=10, -(A) q -for-A1-A2-A3-A4-A5-A6-A7-A8-A9-A 10 -; when q = 11, -(A) q -for-A1-A2-A3-A4-A5-A6-A7-A8-A9-A 10 -A 11 -; when q = 12, -(A) q -for-A1-A2-A3-A4-A5-A6-A7-A8-A9-A 10 -A 11 -A 12 -; when q = 13, -(A) q -for-A1-A2-A3-A4-A5-A6-A7-A8-A9-A 10 -A 11 -A 12 -A 13 -; and when q = 14, -(A) q -for-A1-A2-A3-A4-A5-A6-A7-A8-A9-A 10 -A 11 -A 12 -A 13 -A 14 -.

[0146] In some embodiments, q=4 and R 1 A chemical moiety represented by the formula: -A1-A2-A3-A4-, wherein A 1-4 Each of which is independently selected from the group consisting of: O, S, SO, SO2, NR 1c 、SO2NR 1c ,SONR1c 、SO(=NR 1c ), SO(=NR 1c )NR 1d 、CONR 1c NR 1c CONR 1d NR 1c C(O)O、NR 1c SO2NR 1d , CO, CR 1a =CR 1b 、C≡C、SiR 1a R 1b 、P(O)R 1a 、P(O)OR 1a 、(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 O(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 S(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 NR(CR 1a R 1b ) 1-4 , optionally substituted 3-11 membered cycloalkyl, 3-11 membered heterocyclyl, aryl and heteroaryl;

[0147] where R 1a and R 1beach independently selected from the group consisting of: -H, D, -halo, -C1-C8 alkyl, -O-C1-C8 alkyl, -C1-C6 haloalkyl, -S-C1-C8 alkyl, -NHC1-C8 alkyl, -N(C1-C8 alkyl)2, 3-11 membered cycloalkyl, aryl, heteroaryl, 3-11 membered heterocyclyl, -O-(3-11 membered cycloalkyl), -S-(3-11 membered cycloalkyl), NH-(3-11 membered cycloalkyl), N(3-11 membered cycloalkyl)2, N-(3-11 membered cycloalkyl) C1-C8 alkyl), -OH, -NH2, -SH, -SO2C1-C8 alkyl, SO(NH)C1-C8 alkyl, P(O)(OC1-C8 alkyl)(C1-C8 alkyl), -P(O)(OC1-C8 alkyl)2, -C≡C-C1-C8 alkyl, -C≡CH, -CH=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=C(C1-C8 alkyl)2, -Si(OH)3, -Si(C1- C8 alkyl)3, -Si(OH)(C1-C8 alkyl)2, -C(O)C1-C8 alkyl, -CO2H, -CN, -NO2, -SF5, -SO2NHC1-C8 alkyl, -SO2N(C1-C8 alkyl)2, -SO(NH)NHC1-C8 alkyl, -SO(NH)N(C1-C8 alkyl)2, -SONHC1-C8 alkyl, -SON(C1-C8 alkyl)2, -CONHC1-C8 alkyl, -CON(C1-C8 alkyl)2, -N(C1- C8 alkyl)CONH(C1-C8 alkyl), -N(C1-C8 alkyl)CON(C1-C8 alkyl)2, -NHCONH(C1-C8 alkyl), -NHCON(C1-C8 alkyl)2, -NHCONH2, -N(C1-C8 alkyl)SO2NH(C1-C8 alkyl), -N(C1-C8 alkyl)SO2N(C1-C8 alkyl)2, -NHSO2NH(C1-C8 alkyl), -NHSO2N(C1-C8 alkyl)2, or -NHSO2NH2; and

[0148] R 1c and R 1d are each independently selected from the group consisting of: H, D, optionally substituted C 1-4 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, aryl or heteroaryl.

[0149] In other embodiments, q=3 and R 1 A chemical moiety represented by the formula: -A1-A2-A3-, wherein A 1-3Each of which is independently selected from the group consisting of: O, S, SO, SO2, NR 1c 、SO2NR 1c ,SONR 1c 、SO(=NR 1c ), SO(=NR 1c )NR 1d 、CONR 1c NR 1c CONR 1d NR 1c C(O)O、NR 1c SO2NR 1d , CO, CR 1a =CR 1b 、C≡C、SiR 1a R 1b 、P(O)R 1a 、P(O)OR 1a 、(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 O(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 S(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 NR(CR 1a R 1b ) 1-4 , optionally substituted 3-11 membered cycloalkyl, 3-11 membered heterocyclyl, aryl and heteroaryl;

[0150] where R 1a and R 1beach independently selected from the group consisting of: -H, D, -halo, -C1-C8 alkyl, -O-C1-C8 alkyl, -C1-C6 haloalkyl, -S-C1-C8 alkyl, -NHC1-C8 alkyl, -N(C1-C8 alkyl)2, 3-11 membered cycloalkyl, aryl, heteroaryl, 3-11 membered heterocyclyl, -O-(3-11 membered cycloalkyl), -S-(3-11 membered cycloalkyl), NH-(3-11 membered cycloalkyl), N(3-11 membered cycloalkyl)2, N-(3-11 membered cycloalkyl) C1-C8 alkyl), -OH, -NH2, -SH, -SO2C1-C8 alkyl, SO(NH)C1-C8 alkyl, P(O)(OC1-C8 alkyl)(C1-C8 alkyl), -P(O)(OC1-C8 alkyl)2, -C≡C-C1-C8 alkyl, -C≡CH, -CH=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=C(C1-C8 alkyl)2, -Si(OH)3, -Si(C1- C8 alkyl)3, -Si(OH)(C1-C8 alkyl)2, -C(O)C1-C8 alkyl, -CO2H, -CN, -NO2, -SF5, -SO2NHC1-C8 alkyl, -SO2N(C1-C8 alkyl)2, -SO(NH)NHC1-C8 alkyl, -SO(NH)N(C1-C8 alkyl)2, -SONHC1-C8 alkyl, -SON(C1-C8 alkyl)2, -CONHC1-C8 alkyl, -CON(C1-C8 alkyl)2, -N(C1- C8 alkyl)CONH(C1-C8 alkyl), -N(C1-C8 alkyl)CON(C1-C8 alkyl)2, -NHCONH(C1-C8 alkyl), -NHCON(C1-C8 alkyl)2, -NHCONH2, -N(C1-C8 alkyl)SO2NH(C1-C8 alkyl), -N(C1-C8 alkyl)SO2N(C1-C8 alkyl)2, -NHSO2NH(C1-C8 alkyl), -NHSO2N(C1-C8 alkyl)2, or -NHSO2NH2; and

[0151] R 1c and R 1d are each independently selected from the group consisting of: H, D, optionally substituted C 1-4 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, aryl or heteroaryl.

[0152] In other embodiments, q=2 and R 1 A chemical moiety represented by the formula: -A1-A2-, wherein A 1-2Each of which is independently selected from the group consisting of: O, S, SO, SO2, NR 1c 、SO2NR 1c ,SONR 1c 、SO(=NR 1c ), SO(=NR 1c )NR 1d 、CONR 1c NR 1c CONR 1d NR 1c C(O)O、NR 1c SO2NR 1d , CO, CR 1a =CR 1b 、C≡C、SiR 1a R 1b 、P(O)R 1a 、P(O)OR 1a 、(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 O(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 S(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 NR(CR 1a R 1b ) 1-4 , optionally substituted 3-11 membered cycloalkyl, 3-11 membered heterocyclyl, aryl and heteroaryl;

[0153] where R 1a and R 1beach independently selected from the group consisting of: -H, D, -halo, -C1-C8 alkyl, -O-C1-C8 alkyl, -C1-C6 haloalkyl, -S-C1-C8 alkyl, -NHC1-C8 alkyl, -N(C1-C8 alkyl)2, 3-11 membered cycloalkyl, aryl, heteroaryl, 3-11 membered heterocyclyl, -O-(3-11 membered cycloalkyl), -S-(3-11 membered cycloalkyl), NH-(3-11 membered cycloalkyl), N(3-11 membered cycloalkyl)2, N-(3-11 membered cycloalkyl) C1-C8 alkyl), -OH, -NH2, -SH, -SO2C1-C8 alkyl, SO(NH)C1-C8 alkyl, P(O)(OC1-C8 alkyl)(C1-C8 alkyl), -P(O)(OC1-C8 alkyl)2, -C≡C-C1-C8 alkyl, -C≡CH, -CH=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=C(C1-C8 alkyl)2, -Si(OH)3, -Si(C1- C8 alkyl)3, -Si(OH)(C1-C8 alkyl)2, -C(O)C1-C8 alkyl, -CO2H, -CN, -NO2, -SF5, -SO2NHC1-C8 alkyl, -SO2N(C1-C8 alkyl)2, -SO(NH)NHC1-C8 alkyl, -SO(NH)N(C1-C8 alkyl)2, -SONHC1-C8 alkyl, -SON(C1-C8 alkyl)2, -CONHC1-C8 alkyl, -CON(C1-C8 alkyl)2, -N(C1- C8 alkyl)CONH(C1-C8 alkyl), -N(C1-C8 alkyl)CON(C1-C8 alkyl)2, -NHCONH(C1-C8 alkyl), -NHCON(C1-C8 alkyl)2, -NHCONH2, -N(C1-C8 alkyl)SO2NH(C1-C8 alkyl), -N(C1-C8 alkyl)SO2N(C1-C8 alkyl)2, -NHSO2NH(C1-C8 alkyl), -NHSO2N(C1-C8 alkyl)2, or -NHSO2NH2; and

[0154] R 1c and R 1d are each independently selected from the group consisting of: H, D, optionally substituted C 1-4 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, aryl or heteroaryl.

[0155] In other embodiments, q=1 and R 1 A chemical moiety represented by the formula: -A1-, wherein A1 is selected from the group consisting of: O, S, SO, SO2, NR 1c、SO2NR 1c ,SONR 1c 、SO(=NR 1c ), SO(=NR 1c )NR 1d 、CONR 1c NR 1c CONR 1d NR 1c C(O)O、NR 1c SO2NR 1d , CO, CR 1a =CR 1b 、C≡C、SiR 1a R 1b 、P(O)R 1a 、P(O)OR 1a 、(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 O(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 S(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 NR(CR 1a R 1b ) 1-4 , optionally substituted 3-11 membered cycloalkyl, 3-11 membered heterocyclyl, aryl and heteroaryl;

[0156] where R 1a and R 1beach independently selected from the group consisting of: -H, D, -halo, -C1-C8 alkyl, -O-C1-C8 alkyl, -C1-C6 haloalkyl, -S-C1-C8 alkyl, -NHC1-C8 alkyl, -N(C1-C8 alkyl)2, 3-11 membered cycloalkyl, aryl, heteroaryl, 3-11 membered heterocyclyl, -O-(3-11 membered cycloalkyl), -S-(3-11 membered cycloalkyl), NH-(3-11 membered cycloalkyl), N(3-11 membered cycloalkyl)2, N-(3-11 membered cycloalkyl) C1-C8 alkyl), -OH, -NH2, -SH, -SO2C1-C8 alkyl, SO(NH)C1-C8 alkyl, P(O)(OC1-C8 alkyl)(C1-C8 alkyl), -P(O)(OC1-C8 alkyl)2, -C≡C-C1-C8 alkyl, -C≡CH, -CH=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=C(C1-C8 alkyl)2, -Si(OH)3, -Si(C1- C8 alkyl)3, -Si(OH)(C1-C8 alkyl)2, -C(O)C1-C8 alkyl, -CO2H, -CN, -NO2, -SF5, -SO2NHC1-C8 alkyl, -SO2N(C1-C8 alkyl)2, -SO(NH)NHC1-C8 alkyl, -SO(NH)N(C1-C8 alkyl)2, -SONHC1-C8 alkyl, -SON(C1-C8 alkyl)2, -CONHC1-C8 alkyl, -CON(C1-C8 alkyl)2, -N(C1- C8 alkyl)CONH(C1-C8 alkyl), -N(C1-C8 alkyl)CON(C1-C8 alkyl)2, -NHCONH(C1-C8 alkyl), -NHCON(C1-C8 alkyl)2, -NHCONH2, -N(C1-C8 alkyl)SO2NH(C1-C8 alkyl), -N(C1-C8 alkyl)SO2N(C1-C8 alkyl)2, -NHSO2NH(C1-C8 alkyl), -NHSO2N(C1-C8 alkyl)2, or -NHSO2NH2; and

[0157] R 1c and R 1d are each independently selected from the group consisting of: H, D, optionally substituted C 1-4 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, aryl or heteroaryl.

[0158] In some embodiments, R 1 is a covalent bond, optionally with 0-6 R 1a and / or R 1b3-11 membered cycloalkyl substituted with 0-6 R 1a and / or R 1b 3-11 membered heterocyclic group substituted by a group, -(CR 1a R 1b ) 1-5 、-(CR 1a =CR 1b )-、-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(CR 1a =CR 1b )-(CR 1a R 1b ) 1-5 -、-(CR 1a R 1b ) 1-5 -(CR 1a =CR 1b )-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(C≡C)-(CR 1a R 1b ) 1-5 -、-(CR 1a R 1b ) 1-5 -(C≡C)-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c )、-(C≡C)-(CR 1a R 1b) 1-5 -A-(CR 1a R 1b ) 1-5 -(where A is O, S or NR 1c )、-(C≡C)-(CR 1a R 1b ) 1-5 、-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-, -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b 3-11 membered heterocyclic group substituted with a group)-, -(optionally substituted with 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -, -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -、-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-A-, -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-A-, -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 、-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1bsubstituted 3-11-membered cycloalkyl)-A-(wherein A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(wherein A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 、-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-A-(wherein A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(wherein A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(wherein A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A- (wherein each A is independently O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A- (wherein each A is independently O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(CO)(wherein A is O, S or NR 1c),-(CR 1a R 1b ) 1-5 -(CR 1a =CR 1b )-(CR 1a R 1b ) 1-5 -A-(CO)-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(C≡C)-(CR 1a R 1b ) 1-5 -A-(CO)-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-(CO)-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(CO)-(optionally with 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(wherein A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-(CO)-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(CO)-(optionally with 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(wherein A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a and / or R1b substituted 3-11-membered cycloalkyl)-A-(CO)-(wherein each A is independently O, S or NR 1c ), -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-CO-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-(CO)-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-(CO)-(where A is O, S or NR 1c ), -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -, or -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5- .

[0159] In some embodiments, R 1 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CO)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;-(optionally 0-6 R 1a and / or R 1bsubstituted 3-11 membered heterocyclic group)-(CO)-A-(CR 1a R 1b ) 1-5 -, where A is O, S or NR 1c ; -A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-, wherein each A is independently O, S or NR 1c ;-(optionally 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;-(optionally 0-6 R 1a and / or R 1b 3-11 membered heterocyclic group substituted by a group)-(optionally substituted by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;-(optionally 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-A-(CR 1a R 1b ) 1-5 -A-, wherein each A is independently O, S or NR 1c ;-(optionally 0-4 R 1a and / or R 1b (substituted heteroaryl)-A-(CR 1a R 1b ) 1-5 -, where A is O, S or NR 1c ;-(optionally 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CO)-(CR 1a R 1b ) 1-5-A-, where A is O, S or NR 1c ;-(optionally 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;-(optionally 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CO)-A-(CR 1a R 1b ) 1-5 -, where A is O, S or NR 1c ; -(CO)-(optionally substituted with 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c .

[0160] In some embodiments, R 1 -CR 1a =CR 1b -, such as, for example, -CH=CH-.

[0161] In some embodiments, R 1 For-(CR 1a R 1b ) 1-5 , for example -(CH2) 1-5 -, -CH2-, -CH2CH2CH2-, etc.

[0162] In some embodiments, R 1 For-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ), such as, for example, -(CH2) 1-5 -O-, -(CH2) 1-5 -S-, -(CH2) 1-5 -NH- or -(CH2) 0-2 -(C(CH3)2)-(CH2) 0-2 -O-.

[0163] In other embodiments, R 1 For-(CR 1a R 1b ) 1-5-A-(CR 1a R 1b ) 1-5 -(where A is O, S or NR 1c ), such as, for example, -(CH2) 1-5 -O-(CH2) 1-5 -、-(CH2) 1-5 -S-(CH2) 1-5 -、-(CH2) 1-5 -NH-(CH2) 1-5 -.

[0164] In some embodiments, R 1 =-(C≡C)-(CR 1a R 1b ) 1-5 , such as -(C≡C)-(CH2)2- and the like.

[0165] In some embodiments, R 1 For-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b -11-membered cycloalkyl)-, such as, for example, -CH2-cyclobutyl-.

[0166] In some embodiments, R 1 For-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 , such as, for example, -CH2-cyclobutyl-CH2- and the like.

[0167] In some embodiments, R 1 For-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 , such as, for example, -CH2-azetidinyl-CH2-.

[0168] In some embodiments, R 1 For-(CR 1a R1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3- to 11-membered heterocyclyl)-, such as, for example, -CH2-azetidinyl-.

[0169] In some embodiments, R 1 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -, such as, for example, -azetidinyl-CH2-, -pyrrolidinyl-CH2-, -piperidinyl-CH2-, and the like.

[0170] In some embodiments, R 1 For-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ), such as, for example, -CH2-cyclopropyl-CH2-O-, and the like.

[0171] In some embodiments, R 1 For-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ), such as, for example, -CH2-piperidinyl-CH2CH2-O-, and the like.

[0172] In some embodiments, R 1 For-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-A-(wherein A is O, S or NR 1c ), such as, for example, -CH2-azetidinyl-O-, and the like.

[0173] In some embodiments, R 1 For-(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(wherein A is O, S or NR 1c ), such as, for example, -CH2-O-azetidinyl-, -CH2-NH-azetidinyl-, and the like.

[0174] In other embodiments, R 1 For-(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(wherein A is O, S or NR 1c ), such as -CH2-O-cyclobutene-, -CH2-NH-cyclobutene-, and the like.

[0175] In some embodiments, R 1 For-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ), such as, for example, -CH2-O-CH2CH2-O-.

[0176] In some aspects, the compound of Formula IA wherein Y is CR h , where R h is H, and the compound of formula IA has formula IA-1:

[0177]

[0178] where R c1 、R d1 、R e3 , W, Z, B, n and R 1 As described for Formula IA.

[0179] In some embodiments, n in Formula IA-1 is 1.

[0180] In some embodiments of the compound of Formula IA-1, at least one W is optionally substituted -CH2-.

[0181] In some embodiments of the compound of Formula IA-1, at least one W is optionally substituted -CH2-, wherein the optional substituent is alkyl, alkoxy, or alkylamino.

[0182] In some embodiments of the compound of Formula IA-1, at least one W is -CH2-.

[0183] In some embodiments, W in Formula IA-1 is optionally substituted -CH2-, wherein the optional substituent is alkyl, such as, for example, methyl (-CH3), ethyl, propyl, and the like.

[0184] In other embodiments, W in Formula IA-1 is -CH(CH3)-.

[0185] In some embodiments of the compound of Formula IA-1, one W is -C(O)-.

[0186] In some embodiments of the compound of Formula IA-1, one W is -S(O)-.

[0187] In some embodiments of the compound of Formula IA-1, one W is -S(O)2-.

[0188] In some embodiments, B in Formula IA-1 is an optionally substituted 5-7 membered cycloalkyl ring.

[0189] In some embodiments, B in Formula IA-1 is an optionally substituted 5-7 membered cycloalkyl ring, wherein the optional substituent is hydroxy, halo, alkoxy, alkyl, haloalkyl, amino, alkylamino, or cyano.

[0190] In other embodiments, B in Formula IA-1 is an optionally substituted 5-7 membered heterocycle.

[0191] In some embodiments, B in formula IA-1 is an optionally substituted 5-7 membered heterocycle, wherein the optional substituent is hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, or cyano.

[0192] In other aspects, the compound of Formula IA wherein Y is N and Z is CR h , where R h is H, and the compound of Formula IA has Formula IA-2:

[0193]

[0194] where R c1 、R d1 、R e3 , W, B, n and R 1 As described for Formula IA.

[0195] In some embodiments, n in Formula IA-2 is 1.

[0196] In some embodiments of the compound of Formula IA-2, at least one W is optionally substituted -CH2-.

[0197] In some embodiments of the compound of Formula IA-2, at least one W is optionally substituted -CH2-, wherein the optional substituent is alkyl, alkoxy, or alkylamino.

[0198] In some embodiments of the compound of Formula IA-2, at least one W is -CH2-.

[0199] In some embodiments, W in formula IA-2 is optionally substituted -CH2-, wherein the optional substituent is alkyl, such as, for example, methyl (-CH3), ethyl, propyl, and the like.

[0200] In other embodiments, W in Formula IA-2 is -CH(CH3)-.

[0201] In some embodiments of the compound of Formula IA-2, one W is -C(O)-.

[0202] In some embodiments of the compound of Formula IA-2, one W is -S(O)-.

[0203] In some embodiments of the compound of Formula IA-2, one W is -S(O)2-.

[0204] In some embodiments, B in Formula IA-2 is an optionally substituted 5-7 membered heterocycle.

[0205] In some embodiments, B in formula IA-2 is an optionally substituted 5-7 membered heterocycle, wherein the optional substituent is hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, or cyano.

[0206] In other embodiments, B in Formula IA-2 is an optionally substituted 5-7 membered heterocycle.

[0207] In some embodiments, B in Formula IA-2 is an optionally substituted 5-7 membered heterocycle, wherein the optional substituent is hydroxy, halo, alkoxy, alkyl, haloalkyl, amino, alkylamino, or cyano.

[0208] In some aspects, the compound of Formula IA is a compound of Formula IA-3:

[0209]

[0210] wherein m = 1 to 3;

[0211] X is optionally substituted -CH2- or NH; or, if R 1 attached to X, then X is -CH- or N;

[0212] Q is optionally substituted -CH2-, optionally substituted -(CH2)2-, -C(O)-, optionally substituted -CH2C(O)-, -S(O)-, -S(O)2-, optionally substituted -CH2S(O)2-, or optionally substituted -CH2S(O)-; and wherein R c1 、R d1 、R e3 , W, Z, B, n and R 1 As described for Formula IA.

[0213] In some embodiments of compounds of Formula IA-3, n = 1. In other embodiments of compounds of Formula IA-3, n = 2. In other embodiments of compounds of Formula IA-3, n = 3.

[0214] In some embodiments of the compound of Formula IA-3, X is -CH-.

[0215] In other embodiments of the compound of Formula IA-3, X is NH.

[0216] In some of these embodiments of compounds of Formula IA-3, wherein R 1 Attached to X, then X is CH.

[0217] In other embodiments of these embodiments of compounds of Formula IA-3, wherein R 1 Attached to X, then X is N.

[0218] In some embodiments of the compound of Formula IA-3, Q is optionally substituted -CH2-.

[0219] In some embodiments of the compound of Formula IA-3, Q is optionally substituted -CH2-, wherein the optional substituent is alkyl, alkoxy, or alkylamino.

[0220] In some embodiments of the compound of Formula IA-3, Q is optionally substituted -(CH2)2-.

[0221] In some embodiments of the compound of Formula IA-3, Q is optionally substituted -(CH2)2-, wherein the optional substituent is alkyl, alkoxy, or alkylamino.

[0222] In some embodiments of the compound of Formula IA-3, Q is -C(O)-.

[0223] In some embodiments of the compound of Formula IA-3, Q is optionally substituted -CH2C(O)-.

[0224] In some embodiments of the compound of Formula IA-3, Q is -S(O)-.

[0225] In some embodiments of the compound of Formula IA-3, Q is -S(O)2-.

[0226] In some embodiments of the compound of Formula IA-3, Q is optionally substituted -CH2S(O)2-.

[0227] In some embodiments of the compound of Formula IA-3, Q is optionally substituted -CH2S(O)-.

[0228] In some aspects, the compound of formula IA is a compound of formula IA-4

[0229]

[0230] where R k =H, D, F, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-4 Alkoxy, substituted C 1-3 Alkyl, substituted C 1-3 Haloalkyl or substituted C 1-4 Alkoxy; s = 0-7; and m = 1-3; and wherein R c1 、R d1 、R e3 , W, n and R 1 As described for Formula IA.

[0231] In some embodiments of compounds of Formula IA-4, n = 1. In other embodiments of compounds of Formula IA-4, n = 2. In other embodiments of compounds of Formula IA-4, n = 3.

[0232] In some embodiments of compounds of Formula IA-4, m = 1. In other embodiments of compounds of Formula IA-4, m = 2. In other embodiments of compounds of Formula IA-4, m = 3.

[0233] In some embodiments of compounds of Formula IA-4, s = 0. In some embodiments of compounds of Formula IA-4, s = 1. In other embodiments of compounds of Formula IA-4, s = 2. In other embodiments of compounds of Formula IA-4, s = 3.

[0234] In some embodiments of the compound of Formula IA-4, R k =H.

[0235] In some embodiments of the compound of Formula IA-4, R k =D.

[0236] In some embodiments of the compound of Formula IA-4, R k =F.

[0237] In some embodiments of the compound of Formula IA-4, R k =C 1-3 Alkyl, such as C1 alkyl, C2 alkyl, C3 alkyl, -CH3, -CH2CH3 and the like.

[0238] In some embodiments of the compound of Formula IA-4, R k =C 1-3 Haloalkyl, such as C1 haloalkyl, C2 haloalkyl, C3 haloalkyl, -CF3, -CH2CF3 and the like.

[0239] In some embodiments of the compound of Formula IA-4, R k =C 1-4 Alkoxy, such as C1 alkoxy, C2 alkoxy, C3 alkoxy, -OCH3, -OCH2CH3 and the like.

[0240] In some embodiments of the compound of Formula IA-4, R k = substituted C 1-3 Alkyl groups, such as substituted C1 alkyl groups, substituted C2 alkyl groups, substituted C3 alkyl groups, and the like.

[0241] In some embodiments of the compound of Formula IA-4, R k = substituted C 1-3 Haloalkyl, such as substituted C1 haloalkyl, substituted C2 haloalkyl, substituted C3 haloalkyl, and the like.

[0242] In some embodiments of the compound of Formula IA-4, R k = substituted C 1-4 Alkoxy groups, such as substituted C1 alkoxy groups, substituted C2 alkoxy groups, substituted C3 alkoxy groups and the like.

[0243] In some aspects, the compound of Formula IA is a compound of Formula IA-5:

[0244]

[0245] where R k =H, D, F, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-4 Alkoxy; m = 1-3; and s = 0-3, and wherein Rc1 、R d1 、R e3 , W and R 1 As described for Formula IA.

[0246] In some embodiments of compounds of Formula IA-5, m = 1. In other embodiments of compounds of Formula IA-5, m = 2. In other embodiments of compounds of Formula IA-5, m = 3.

[0247] In some embodiments of compounds of Formula IA-5, s = 0. In some embodiments of compounds of Formula IA-5, s = 1. In other embodiments of compounds of Formula IA-5, s = 2. In other embodiments of compounds of Formula IA-5, s = 3.

[0248] In some embodiments of the compound of Formula IA-5, R k =H.

[0249] In some embodiments of the compound of Formula IA-5, R k =D.

[0250] In some embodiments of the compound of Formula IA-5, R k =F.

[0251] In some embodiments of the compound of Formula IA-5, R k =C 1-3 Alkyl, such as C1 alkyl, C2 alkyl, C3 alkyl, -CH3, -CH2CH3 and the like.

[0252] In some embodiments of the compound of Formula IA-5, R k =C 1-3 Haloalkyl, such as C1 haloalkyl, C2 haloalkyl, C3 haloalkyl, -CF3, -CH2CF3 and the like.

[0253] In some embodiments of the compound of Formula IA-5, R k =H or C 1-4 Alkoxy, such as C1 alkoxy, C2 alkoxy, C3 alkoxy, -OCH3, -OCH2CH3 and the like.

[0254] In some aspects, the compound of Formula IA is a compound of Formula IA-6:

[0255]

[0256] where R k =H, D, F, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-4Alkoxy; and s = 0-3, and wherein R c1 、R d1 、R e3 and R 1 As described for Formula IA.

[0257] In some embodiments of compounds of Formula IA-6, s = 0. In some embodiments of compounds of Formula IA-6, s = 1. In other embodiments of compounds of Formula IA-6, s = 2. In other embodiments of compounds of Formula IA-6, s = 3.

[0258] In some embodiments of the compound of Formula IA-6, R k =H.

[0259] In some embodiments of the compound of Formula IA-6, R k =D.

[0260] In some embodiments of the compound of Formula IA-6, R k =F.

[0261] In some embodiments of the compound of Formula IA-6, R k =C 1-3 Alkyl, such as C1 alkyl, C2 alkyl, C3 alkyl, -CH3, -CH2CH3 and the like.

[0262] In some embodiments of the compound of Formula IA-6, R k =C 1-3 Haloalkyl, such as C1 haloalkyl, C2 haloalkyl, C3 haloalkyl, -CF3, -CH2CF3 and the like.

[0263] In some embodiments of the compound of Formula IA-6, R k =H or C 1-4 Alkoxy, such as C1 alkoxy, C2 alkoxy, C3 alkoxy, -OCH3, -OCH2CH3 and the like.

[0264] In some aspects, the ULM moiety in the compounds of the present disclosure is a small molecule E3 ubiquitin ligase binding moiety that binds to von Hippel-Lindau E3 ubiquitin ligase (VHL). Such ULM moieties that bind to VHL are known to those skilled in the art. Methods for determining whether a small molecule binds to von Hippel-Lindau E3 ubiquitin ligase are known in the art.

[0265] In some embodiments, the ULM is a previously described ULM.

[0266] In some embodiments, the ULM is a ULM portion described in U.S. Patent Application Publication No. 2019 / 0300521, the entire contents of which are incorporated herein by reference.

[0267] In other embodiments, the ULM is a ULM portion described in U.S. Patent Application Publication No. 2019 / 0255066, the entire contents of which are incorporated herein by reference.

[0268] In other embodiments, the ULM is a ULM moiety described in WO 2019 / 084030, the entire contents of which are incorporated herein by reference.

[0269] In other embodiments, the ULM is a ULM moiety described in WO 2019 / 084026, the entire contents of which are incorporated herein by reference.

[0270] In some embodiments, ULM is a moiety having formula ULM-I

[0271]

[0272] in

[0273] -------Indicates ULM and R 1 Attachment location;

[0274] V is H or F;

[0275] R 3 is optionally substituted phenyl, optionally substituted naphthyl or optionally substituted 5-10 membered heteroaryl;

[0276] R 4 or R 5 One of them is H, D, haloalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, -COR d 、CONR e1 R e2 ;

[0277] R 4 or R 5 The other of is H or D;

[0278] or R 4 and R 5 Together with the carbon atoms to which they are both attached, they form an optionally substituted 3-5 membered cycloalkyl or heterocyclyl;

[0279] W 3 is optionally substituted aryl, optionally substituted heteroaryl, or

[0280]

[0281] R 6 and R 7 are independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted haloalkyl,

[0282] or R 6 、R 7 and the carbon atom to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl;

[0283] R 8 is an optionally substituted heterocyclic group, an optionally substituted heteroaryl group, an optionally substituted aryl group, -C(O)NR a R b 、-NR a R b 、

[0284] R a is selected from H or optionally substituted alkyl;

[0285] R b Selected from H; -C(O)-*, wherein * and R 1 optionally substituted alkyl; optionally substituted alkylcarbonyl; optionally substituted (cycloalkyl)alkylcarbonyl; optionally substituted aralkylcarbonyl; optionally substituted arylcarbonyl; optionally substituted (cycloalkyl)carbonyl; optionally substituted (heterocyclyl)carbonyl or optionally substituted aralkyl;

[0286] Each R c are independently H, halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, or haloalkoxy;

[0287] Each R d are independently selected from H, optionally substituted alkyl or NR e1 R e2 ;

[0288] Each R e1 and R e2 are independently H, D, optionally substituted alkyl, or R e1 and R e2 Together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic group; and

[0289] p is 0, 1, 2, 3 or 4.

[0290] In some embodiments of ULM-1, V is H.

[0291] In other embodiments of ULM-1, V is F.

[0292] In some embodiments of ULM-1, R 3 is an optionally substituted phenyl group having the formula:

[0293]

[0294] in

[0295] R 9 H, D, halide, -CN, -OH, -NO2, -NR e1 R e2 、-OR e1 、-CONR e1 R e2 、-NR e1 COR e2 、-SO2NR e1 R e2 、-NR e1 SO2R e2 , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted haloalkyl, optionally substituted haloalkoxy; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted cycloalkyl; or optionally substituted heterocyclyl;

[0296] R 10 is H, D, halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, optionally substituted alkoxy, or optionally substituted haloalkoxy; and

[0297] z is 0, 1, 2, 3 or 4.

[0298] In some embodiments, wherein R 3 is an optionally substituted phenyl group, R 10 It is -F or -OCH3.

[0299] In some embodiments, wherein R 3 is an optionally substituted phenyl group, R 9 It is -CN.

[0300] In some embodiments, wherein R 3 is an optionally substituted phenyl group, R 9 is an optionally substituted heteroaryl group.

[0301] In some embodiments, wherein R 3 is an optionally substituted phenyl group, R 9 for

[0302] Each of them is optionally substituted.

[0303] In other embodiments, wherein R 3 is an optionally substituted phenyl group, R9 for

[0304]

[0305] In other embodiments, wherein R 3 is an optionally substituted phenyl group, R 9 for

[0306]

[0307] In other embodiments, R 3 for

[0308]

[0309] In some embodiments, wherein R 3 is an optionally substituted phenyl group, R 10 is hydroxy, halogen, -NH(C1-C4 alkyl) or C1-C6 alkoxy, and z is 0, 1, 2, 3 or 4.

[0310] In some embodiments of ULM-1, R 4 or R 5 One of them is H, and R 4 or R 5 The other of is H or optionally substituted alkyl.

[0311] In other embodiments of ULM-1, R 4 or R 5 One of them is H, and R 4 or R 5 The other of the group is an optionally substituted C1-C6 alkyl group.

[0312] In other embodiments of ULM-1, R 4 or R 5 One of them is H, and R 4 or R 5 The other one of them is C1-C6 alkyl.

[0313] In other embodiments of ULM-1, R 4 or R 5 One of them is H, and R 4 or R 5 The other is -CH3.

[0314] In other embodiments of ULM-1, R 4 or R 5 One of them is H, and R 4 or R 5 The other one is -CH2OH.

[0315] In other embodiments of ULM-1, R 4 and R 5 Both are H.

[0316] In some embodiments of ULM-1, W 3 for

[0317]

[0318] In some embodiments of ULM-1, R 6 For H.

[0319] In some embodiments of ULM-1, R 7 is H or optionally substituted alkyl.

[0320] In some embodiments of ULM-1, R 7 For H.

[0321] In some embodiments of ULM-1, R 7 is an optionally substituted alkyl group.

[0322] In some embodiments of ULM-1, R 7 is an optionally substituted C1-C6 alkyl group.

[0323] In some embodiments of ULM-1, R 7 It is a C1-C6 alkyl group.

[0324] In some embodiments of ULM-1, R 7 C 1- C6 alkyl-OH, C 1- C6 alkyl-NH2, -C 1- C6 alkyl-CONH-* or -C 1- C6 alkyl-NHCO-* (where * is the same as R 1 attachment point).

[0325] In some embodiments of ULM-1, R 7 is tert-butyl or isopropyl.

[0326] In some embodiments of ULM-1, R 7 It is tert-butyl.

[0327] In some embodiments of ULM-1, R 7 It is -isopropyl.

[0328] In some embodiments of ULM-1, R 8 NR a R b .

[0329] In some embodiments, R a is H or optionally substituted alkyl.

[0330] In some embodiments, R a For H.

[0331] In some embodiments, R b is H, optionally substituted alkyl, -C(O)-* (wherein * is the same as R 1 Attachment point), optionally substituted (cycloalkyl)carbonyl or optionally substituted alkylcarbonyl.

[0332] In some embodiments, R b is an optionally substituted alkylcarbonyl group.

[0333] In some embodiments, R b -C(O)-*, where * is the same as R 1 attachment point.

[0334] In some embodiments of ULM-1, R 8 CONR a R b .

[0335] In some embodiments of ULM-1, R 8 for Where * is the same as R 1 attachment point.

[0336] In some embodiments of ULM-1, R 8 for Where * is the same as R 1 attachment point.

[0337] In some embodiments of ULM-1, R 8 for Where * is the same as R 1 attachment point.

[0338] In some embodiments of ULM-1, R 8 for

[0339] In some embodiments, R 8 -NH-*, where * is the same as R 1 attachment point.

[0340] In some embodiments of ULM-1, R 8 is an optionally substituted heteroaryl group.

[0341] In some embodiments of ULM-1, R8 for Each R c is independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl or haloalkoxy, and p is 0, 1 or 2.

[0342] In some embodiments, R 8 for Each R c is independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl or haloalkoxy, and p is 0, 1 or 2.

[0343] In some embodiments, R 8 for Where * is the same as R 1 attachment point.

[0344] In some embodiments, R 8 for

[0345] In some embodiments, R 8 for

[0346] In some embodiments, R 8 for

[0347] In some embodiments, R 8 for

[0348] In some embodiments, R 8 for

[0349] In some embodiments, R 8 for

[0350] In some embodiments, R 8 for

[0351] In some embodiments, R 8 for

[0352] In some embodiments, R 8 for

[0353] In some embodiments, ULM-1 is a compound of the formula:

[0354]

[0355] *For ULM and R 1 attachment point.

[0356] In some embodiments of ULM-IA, ULM-IB, ULM-IC, or ULM-ID, R 9 is optionally substituted and

[0357] And R 10 H, D, hydroxyl, halogen, amino C 1-4 Alkyl or C 1-4 Alkyloxy.

[0358] In some embodiments, ULM is a moiety having the formula ULM-II

[0359]

[0360] in

[0361] -------Indicates ULM and R 1 Attachment location;

[0362] R 14 is C1-C6 alkyl, such as, for example, -CH3, -CH2CH3, -CH(CH3)2, and the like; and all other variables have the same ranges as described above for ULM-1.

[0363] In some embodiments, R in ULM-II 14 In other embodiments, R in ULM-II 14 It is -CH(CH3)2.

[0364] In some aspects, the compounds of Formula I are those having Formula IA-7 or IA-8:

[0365]

[0366]

[0367] Where V is H or F;

[0368] W is optionally substituted -CH2-, -C(O)-, -S(O)-, or -S(O)2-; wherein when n=2 or 3, only one W can be -C(O)-, -S(O)-, or -S(O)2-;

[0369] n = 0-3;

[0370] m = 1-3;

[0371] R k =H, D, F, C 1-3Alkyl, C 1-3 Haloalkyl or C 1-4 alkoxy;

[0372] R c1 and R d1 are independently H, D, halo, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-4 alkoxy;

[0373] R e3 H, -C(O)R f OR-P(O)(OR g )2; where R f and R g Independently H, C 1-4 Alkyl, C 1-4 Substituted alkyl, C 3-8 Cycloalkyl, C 3-8 Substituted cycloalkyl, C 3-8 Heterocycloalkyl or C 3-8 substituted heterocycloalkyl;

[0374] R 1 is a covalent bond, optionally with 0-6 R 1a and / or R 1b 3-11 membered cycloalkyl substituted with 0-6 R 1a and / or R 1b 3-11 membered heterocyclic group substituted by a group, -(CR 1a R 1b ) 1-5 、-(CR 1a =CR 1b )-、-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(CR1a =CR 1b )-(CR 1a R 1b ) 1-5 -、-(CR 1a R 1b ) 1-5 -(CR 1a =CR 1b )-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(C≡C)-(CR 1a R 1b ) 1-5 -、-(CR 1a R 1b ) 1-5 -(C≡C)-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c )、-(C≡C)-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -(where A is O, S or NR 1c )、-(C≡C)-(CR 1a R 1b ) 1-5 、-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-, -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b 3-11 membered heterocyclic group substituted with a group)-, -(optionally substituted with 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -, -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR1a R 1b ) 1-5 -、-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-A-, -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-A-, -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 、-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-A-(wherein A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(wherein A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 、-(CR 1a R1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-A-(wherein A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(wherein A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(wherein A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A- (wherein each A is independently O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a and / or R 1bsubstituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A- (wherein each A is independently O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(CO)(wherein A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(CR 1a =CR 1b )-(CR 1a R 1b ) 1-5 -A-(CO)-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(C≡C)-(CR 1a R 1b ) 1-5 -A-(CO)-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-(CO)-(where A is O, S or NR 1c ),-(CR 1a R1b ) 1-5 -A-(CO)-(optionally with 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(wherein A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-(CO)-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(CO)-(optionally with 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(wherein A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-A-(CO)-(wherein each A is independently O, S or NR 1c ), -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-CO-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-(CO)-(where A is O, S or NR 1c ), -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR1c );-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-(CO)-(where A is O, S or NR 1c ), -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -or-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -;

[0375] R 4 is H, optionally substituted alkyl, optionally substituted C1-C6 alkyl or -CH3;

[0376] R 7 is an optionally substituted alkyl group, preferably an optionally substituted C1-C6 alkyl group, and more preferably a C1-C6 alkyl group; and

[0377] R 9 H, D, halide, -CN, -OH, -NO2, -NR e1 R e2 、-OR e1 、-CONR e1 R e2 、-NR e1 COR e2 、-SO2NR e1 R e2 、-NR e1 SO2R e2 , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted haloalkyl, optionally substituted haloalkoxy; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted cycloalkyl; or optionally substituted heterocyclyl;

[0378] R 1a 、R 1b 、R 1c and R 1eEach is independently -H, D, -halo, -C1-C8 alkyl, -C1-C6 haloalkyl, -O-C1-C8 alkyl, -S-C1-C8 alkyl, -NHC1-C8 alkyl, -N(C1-C8 alkyl)2, 3-11 membered cycloalkyl, aryl, heteroaryl, 3-11 membered heterocyclyl, -O-(3-11 membered cycloalkyl), -S-(3-11 membered cycloalkyl), NH-(3-11 membered cycloalkyl), N(3-11 membered cycloalkyl)2, N-(3-11 membered cycloalkyl)(C1-C8 alkyl), -OH, -NH 2, -SH, -SO2C1-C8 alkyl, SO(NH)C1-C8 alkyl, P(O)(OC1-C8 alkyl)(C1-C8 alkyl), -P(O)(OC1-C8 alkyl)2, -C≡C-C1-C8 alkyl, -C≡CH, -CH=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=C(C1-C8 alkyl)2, -Si(OH)3, -Si(C1-C8 alkyl)3, -Si(OH)(C1-C 8 alkyl)2, -C(O)C1-C8 alkyl, -CO2H, -CN, -CF3, -CHF2, -CH2F, -NO2, -SF5, -SO2NHC1-C8 alkyl, -SO2N(C1-C8 alkyl)2, -SO(NH)NHC1-C8 alkyl, -SO(NH)N(C1-C8 alkyl)2, -SONHC1-C8 alkyl, -SON(C1-C8 alkyl)2, -CONHC1-C8 alkyl, -CON(C1-C8 alkyl)2, -N(C1-C8 alkyl)CO NH(C1-C8 alkyl), -N(C1-C8 alkyl)CON(C1-C8 alkyl)2, -NHCONH(C1-C8 alkyl), -NHCON(C1-C8 alkyl)2, -NHCONH2, -N(C1-C8 alkyl)SO2NH(C1-C8 alkyl), -N(C1-C8 alkyl)SO2N(C1-C8 alkyl)2, -NHSO2NH(C1-C8 alkyl), -NHSO2N(C1-C8 alkyl)2, or -NHSO2NH2; or, where the context permits, R 1a or R 1b connected to other groups, or to each other, to form a group optionally with 0-4 R 1e substituted cycloalkyl and / or heterocyclyl moieties; and

[0379] Each R e1 and R e2 are independently H, D, optionally substituted alkyl, or R e1 and R e2 Together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic group.

[0380] In some aspects, the compounds of Formula I are those having Formula IA-9 or IA-10:

[0381]

[0382] Where V is H or F;

[0383] W is optionally substituted -CH2-, -C(O)-, -S(O)-, or -S(O)2-; wherein when n=2 or 3, only one W can be -C(O)-, -S(O)-, or -S(O)2-;

[0384] n = 0-3;

[0385] m = 1-3;

[0386] R k =H, D, F, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-4 alkoxy;

[0387] s=0-3;

[0388] R c1 and R d1 are independently H, D, halo, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-4 alkoxy;

[0389] R e3 H, -C(O)R f OR-P(O)(OR g )2; where R f and R g Independently H, C 1-4 Alkyl, C 1-4 Substituted alkyl, C 3-8 Cycloalkyl, C 3-8 Substituted cycloalkyl, C 3-8 Heterocycloalkyl or C 3-8 substituted heterocycloalkyl;

[0390] R 1 is a covalent bond, optionally with 0-6 R 1a and / or R 1b 3-11 membered cycloalkyl substituted with 0-6 R 1a and / or R 1b 3-11 membered heterocyclic group substituted by a group, -(CR 1a R 1b ) 1-5 、-(CR 1a =CR 1b )-、-(CR1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(CR 1a =CR 1b )-(CR 1a R 1b ) 1-5 -、-(CR 1a R 1b ) 1-5 -(CR 1a =CR 1b )-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(C≡C)-(CR 1a R 1b ) 1-5 -、-(CR 1a R 1b ) 1-5 -(C≡C)-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c )、-(C≡C)-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -(where A is O, S or NR 1c )、-(C≡C)-(CR 1a R 1b ) 1-5 、-(CR1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-, -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b 3-11 membered heterocyclic group substituted with a group)-, -(optionally substituted with 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -, -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -、-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-A-, -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-A-, -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 、-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-A-(wherein A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1aR 1b ) 1-5 -A-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(wherein A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 、-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c 、-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-A-(wherein A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(wherein A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R1a and / or R 1b substituted 3-11-membered cycloalkyl)-(wherein A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A- (wherein each A is independently O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A- (wherein each A is independently O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(CO)(wherein A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(CR 1a =CR 1b )-(CR 1a R 1b ) 1-5 -A-(CO)-(where A is O, S or NR 1c),-(CR 1a R 1b ) 1-5 -(C≡C)-(CR 1a R 1b ) 1-5 -A-(CO)-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-(CO)-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(CO)-(optionally with 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(wherein A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-(CO)-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(CO)-(optionally with 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(wherein A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-A-(CO)-(wherein each A is independently O, S or NR 1c ), -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-CO-(CR 1a R 1b ) 1-5-A-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-(CO)-(where A is O, S or NR 1c ),-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-(CO)-(where A is O, S or NR 1c ), -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -or-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5- ; or R 1 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CO)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;-(optionally 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CO)-A-(CR 1a R 1b ) 1-5 -, where A is O, S or NR 1c ; -A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-, wherein each A is independently O, S or NR1c ;-(optionally 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;-(optionally 0-6 R 1a and / or R 1b 3-11 membered heterocyclic group substituted by a group)-(optionally substituted by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;-(optionally 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-A-(CR 1a R 1b ) 1-5 -A-, wherein each A is independently O, S or NR 1c ;-(optionally 0-4 R 1a and / or R 1b (substituted heteroaryl)-A-(CR 1a R 1b ) 1-5 -, where A is O, S or NR 1c ;-(optionally 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;-(optionally 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CO)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;-(optionally 0-6 R 1a and / or R 1bsubstituted 3-11-membered cycloalkyl)-(CO)-A-(CR 1a R 1b ) 1-5 -, where A is O, S or NR 1c ; -(CO)-(optionally substituted with 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;

[0391] R 4 is H, optionally substituted alkyl, optionally substituted C1-C6 alkyl or -CH3;

[0392] R 7 is an optionally substituted alkyl group, preferably an optionally substituted C1-C6 alkyl group, and more preferably a C1-C6 alkyl group; and

[0393] R 9 H, D, halide, -CN, -OH, -NO2, -NR e1 R e2 、-OR e1 、-CONR e1 R e2 、-NR e1 COR e2 、-SO2NR e1 R e2 、-NR e1 SO2R e2 , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted haloalkyl, optionally substituted haloalkoxy; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted cycloalkyl; or optionally substituted heterocyclyl;

[0394] R 1a 、R 1b 、R 1c and R 1eEach is independently -H, D, -halo, -C1-C8 alkyl, -C1-C6 haloalkyl, -O-C1-C8 alkyl, -S-C1-C8 alkyl, -NHC1-C8 alkyl, -N(C1-C8 alkyl)2, 3-11 membered cycloalkyl, aryl, heteroaryl, 3-11 membered heterocyclyl, -O-(3-11 membered cycloalkyl), -S-(3-11 membered cycloalkyl), NH-(3-11 membered cycloalkyl), N(3-11 membered cycloalkyl)2, N-(3-11 membered cycloalkyl)(C1-C8 alkyl), -OH, -NH 2, -SH, -SO2C1-C8 alkyl, SO(NH)C1-C8 alkyl, P(O)(OC1-C8 alkyl)(C1-C8 alkyl), -P(O)(OC1-C8 alkyl)2, -C≡C-C1-C8 alkyl, -C≡CH, -CH=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=C(C1-C8 alkyl)2, -Si(OH)3, -Si(C1-C8 alkyl)3, -Si(OH)(C1-C 8 alkyl)2, -C(O)C1-C8 alkyl, -CO2H, -CN, -CF3, -CHF2, -CH2F, -NO2, -SF5, -SO2NHC1-C8 alkyl, -SO2N(C1-C8 alkyl)2, -SO(NH)NHC1-C8 alkyl, -SO(NH)N(C1-C8 alkyl)2, -SONHC1-C8 alkyl, -SON(C1-C8 alkyl)2, -CONHC1-C8 alkyl, -CON(C1-C8 alkyl)2, -N(C1-C8 alkyl)CO NH(C1-C8 alkyl), -N(C1-C8 alkyl)CON(C1-C8 alkyl)2, -NHCONH(C1-C8 alkyl), -NHCON(C1-C8 alkyl)2, -NHCONH2, -N(C1-C8 alkyl)SO2NH(C1-C8 alkyl), -N(C1-C8 alkyl)SO2N(C1-C8 alkyl)2, -NHSO2NH(C1-C8 alkyl), -NHSO2N(C1-C8 alkyl)2, or -NHSO2NH2; or, where the context permits, R 1a or R 1b connected to other groups, or to each other, to form a group optionally with 0-4 R 1e substituted cycloalkyl and / or heterocyclyl moieties; and

[0395] Each R e1 and R e2 are independently H, D, optionally substituted alkyl, or R e1 and R e2 Together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic group.

[0396] In some embodiments of compounds of Formula IA-9 or IA-10, n = 1. In other embodiments of compounds of Formula IA-9 or IA-10, n = 2. In other embodiments of compounds of Formula IA-9 or IA-10, n = 3.

[0397] In some embodiments of compounds of Formula IA-7 or IA-8, m = 1. In other embodiments of compounds of Formula IA-7 or IA-8, m = 2. In other embodiments of compounds of Formula IA-7 or IA-8, m = 3.

[0398] In some embodiments of compounds of Formula IA-9 or IA-10, s = 0. In some embodiments of compounds of Formula IA-9 or IA-10, s = 1. In other embodiments of compounds of Formula IA-9 or IA-10, s = 2. In other embodiments of compounds of Formula IA-9 or IA-10, p = 3.

[0399] In some embodiments of the compound of Formula IA-9 or IA-10, R k =H.

[0400] In some embodiments of the compound of Formula IA-9 or IA-10, R k =D.

[0401] In some embodiments of the compound of Formula IA-9 or IA-10, R k =F.

[0402] In some embodiments of the compound of Formula IA-9 or IA-10, R k =C 1-3 Alkyl, such as C1 alkyl, C2 alkyl, C3 alkyl, -CH3, -CH2CH3 and the like.

[0403] In some embodiments of the compound of Formula IA-9 or IA-10, R k =C 1-3 Haloalkyl, such as C1 haloalkyl, C2 haloalkyl, C3 haloalkyl, -CF3, -CH2CF3 and the like.

[0404] In some embodiments of the compound of Formula IA-9 or IA-10, R k =H or C 1-4 Alkoxy, such as C1 alkoxy, C2 alkoxy, C3 alkoxy, -OCH3, -OCH2CH3 and the like.

[0405] In some embodiments of the compound of Formula IA-9 or IA-10, R c1 and R d1 Each is H.

[0406] In some embodiments of the compound of Formula IA-9 or IA-10, R e3 For H.

[0407] In some embodiments of the compound of Formula IA-9 or IA-10, R c1 、R d1 and R e3 Each is H.

[0408] In some aspects, the compound of Formula I is a compound of Formula IA-9a or IA-10a:

[0409]

[0410] wherein X is N or CH, and the other variables are as described above for Formulas IA-9 and IA-10.

[0411] In some aspects, the compounds of Formula I are those having Formula IA-11 or IA-12:

[0412]

[0413] in

[0414] W is -CH2- or -CH(CH3)-

[0415] X is N or CH;

[0416] R 1 is a covalent bond;

[0417] Optionally 0-6 R 1a and / or R 1b -3-11 membered cycloalkyl substituted by a group;

[0418] Optionally 0-6 R 1a and / or R 1b a 3-11 membered heterocyclic group substituted by a group;

[0419] -(CR 1a R 1b ) 1-5 ;

[0420] -(CR 1a =CR 1b )-;

[0421] -(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;

[0422] -(CR 1a R1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -, where A is O, S or NR 1c ;

[0423] -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;

[0424] -(CR 1a R 1b ) 1-5 -(CR 1a =CR 1b )-(CR 1a R 1b ) 1-5 -;

[0425] -(CR 1a R 1b ) 1-5 -(CR 1a =CR 1b )-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;

[0426] -(CR 1a R 1b ) 1-5 -(C≡C)-(CR 1a R 1b ) 1-5 -;

[0427] -(CR 1a R 1b ) 1-5 -(C≡C)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;

[0428] -(C≡C)-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -, where A is O, S or NR 1c ;

[0429] -(C≡C)-(CR 1a R 1b ) 1-5 ;

[0430] -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-;

[0431] -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-;

[0432] -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -;

[0433] -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;

[0434] -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;

[0435] -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -;

[0436] -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R1b substituted 3-11-membered cycloalkyl)-A-, wherein A is O, S or NR 1c ;

[0437] -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-A-, wherein A is O, S or NR 1c ;

[0438] -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 ;

[0439] -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-A-, wherein A is O, S or NR 1c ;

[0440] -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;

[0441] -(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-, wherein A is O, S or NR 1c ;

[0442] -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1bsubstituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 ;

[0443] -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;

[0444] -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-A-, wherein A is O, S or NR 1c ;

[0445] -(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-, wherein A is O, S or NR 1c ;

[0446] -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;

[0447] -(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-, wherein A is O, S or NR 1c ;

[0448] -(CR 1a R 1b ) 1-5-A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-, wherein each A is independently O, S or NR 1c ;

[0449] -(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-, wherein each A is independently O, S or NR 1c ;

[0450] -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;

[0451] -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-, wherein each A is independently O, S or NR 1c ;

[0452] -(CR 1a R 1b ) 1-5 -A-(CO), where A is O, S or NR 1c ;

[0453] -(CR 1a R 1b ) 1-5 -(CR 1a =CR 1b )-(CR 1a R 1b ) 1-5-A-(CO)-, where A is O, S or NR 1c ;

[0454] -(CR 1a R 1b ) 1-5 -(C≡C)-(CR 1a R 1b ) 1-5 -A-(CO)-, where A is O, S or NR 1c ;

[0455] -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-(CO)-, where A is O, S or NR 1c ;

[0456] -(CR 1a R 1b ) 1-5 -A-(CO)-(optionally with 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-, wherein A is O, S or NR 1c ;

[0457] -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-(CO)-, where A is O, S or NR 1c ;

[0458] -(CR 1a R 1b ) 1-5 -A-(CO)-(optionally with 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-, wherein A is O, S or NR 1c ;

[0459] -(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R1a and / or R 1b substituted 3-11 membered cycloalkyl)-A-(CO)-, wherein each A is independently O, S or NR 1c ;

[0460] -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-CO-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;

[0461] -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-(CO)-, where A is O, S or NR 1c ;

[0462] -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-(CO)-, where A is O, S or NR 1c ;

[0463] -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -;

[0464] -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -;

[0465] -A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1aR 1b ) 1-5 -A-, wherein each A is independently O, S or NR 1c ;

[0466] -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;

[0467] -(optionally replaced by 0-6 R 1a and / or R 1b 3-11 membered heterocyclic group substituted by a group)-(optionally substituted by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;

[0468] -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-A-(CR 1a R 1b ) 1-5 -A-, wherein each A is independently O, S or NR 1c ;

[0469] -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CO)-A-(CR 1a R 1b ) 1-5 -, where A is O, S or NR 1c ;

[0470] -(optionally replaced by 0-4 R 1a and / or R 1b (substituted heteroaryl)-A-(CR 1a R 1b ) 1-5 -, where A is O, S or NR 1c ;

[0471] -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CO)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;

[0472] -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CO)-A-(CR 1a R 1b ) 1-5 -, where A is O, S or NR 1c ;or

[0473] -(CO)-(optionally with 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;

[0474] R 4 is H, -CH3 or -CH2OH;

[0475] R 7 is C1-C6 alkyl, preferably -C(CH3)3 or -CH(CH3)2; and

[0476] R 9 is -CN or optionally substituted heteroaryl, preferably

[0477] R 1a 、R 1b 、R 1c and R 1eEach is independently -H, D, -halo, -C1-C8 alkyl, -C1-C6 haloalkyl, -O-C1-C8 alkyl, -S-C1-C8 alkyl, -NHC1-C8 alkyl, -N(C1-C8 alkyl)2, 3-11 membered cycloalkyl, aryl, heteroaryl, 3-11 membered heterocyclyl, -O-(3-11 membered cycloalkyl), -S-(3-11 membered cycloalkyl), NH-(3-11 membered cycloalkyl), N(3-11 membered cycloalkyl)2, N-(3-11 membered cycloalkyl)(C1-C8 alkyl), -OH, -NH 2, -SH, -SO2C1-C8 alkyl, SO(NH)C1-C8 alkyl, P(O)(OC1-C8 alkyl)(C1-C8 alkyl), -P(O)(OC1-C8 alkyl)2, -C≡C-C1-C8 alkyl, -C≡CH, -CH=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=C(C1-C8 alkyl)2, -Si(OH)3, -Si(C1-C8 alkyl)3, -Si(OH)(C1-C 8 alkyl)2, -C(O)C1-C8 alkyl, -CO2H, -CN, -CF3, -CHF2, -CH2F, -NO2, -SF5, -SO2NHC1-C8 alkyl, -SO2N(C1-C8 alkyl)2, -SO(NH)NHC1-C8 alkyl, -SO(NH)N(C1-C8 alkyl)2, -SONHC1-C8 alkyl, -SON(C1-C8 alkyl)2, -CONHC1-C8 alkyl, -CON(C1-C8 alkyl)2, -N(C1-C8 alkyl)CO NH(C1-C8 alkyl), -N(C1-C8 alkyl)CON(C1-C8 alkyl)2, -NHCONH(C1-C8 alkyl), -NHCON(C1-C8 alkyl)2, -NHCONH2, -N(C1-C8 alkyl)SO2NH(C1-C8 alkyl), -N(C1-C8 alkyl)SO2N(C1-C8 alkyl)2, -NHSO2NH(C1-C8 alkyl), -NHSO2N(C1-C8 alkyl)2, or -NHSO2NH2; or where the context permits, R 1a or R 1b connected to other groups, or to each other, to form a group optionally with 0-4 R 1e The cycloalkyl and / or heterocyclyl moieties are substituted by radicals.

[0478] In some embodiments, W is -CH2-.

[0479] In some embodiments, X is -N.

[0480] In other embodiments, X is -CH.

[0481] In some embodiments, R 4 is -CH3.

[0482] In some embodiments, R 7 It can be -C(CH3)3 or -CH(CH3)2.

[0483] In some embodiments, R k It is -CH3 and s=1.

[0484] In some embodiments, s=0.

[0485] In some embodiments, R 9 for

[0486] In some embodiments of compounds of Formula I, such as Formula IA-11 or Formula IA-12, R 1 for:

[0487] -(CR 1a R 1b ) 1-5 ;

[0488] -(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;

[0489] -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -, where A is O, S or NR 1c ;

[0490] -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CO)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;

[0491] -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CO)-A-(CR 1a R 1b ) 1-5 -, where A is O, S or NR 1c ;

[0492] -(CR1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-A-, wherein A is O, S or NR 1c ;

[0493] -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 ;

[0494] -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;

[0495] -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ; -A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-, wherein each A is independently O, S or NR 1c ;

[0496] -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b )1-5 -A-, where A is O, S or NR 1c ;

[0497] -(optionally replaced by 0-6 R 1a and / or R 1b 3-11 membered heterocyclic group substituted by a group)-(optionally substituted by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;

[0498] -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-A-(CR 1a R 1b ) 1-5 -A-, wherein each A is independently O, S or NR 1c ;

[0499] -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CO)-A-(CR 1a R 1b ) 1-5 -, where A is O, S or NR 1c ;

[0500] -(optionally replaced by 0-4 R 1a and / or R 1b (substituted heteroaryl)-A-(CR 1a R 1b ) 1-5 -, where A is O, S or NR 1c ;

[0501] -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CO)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c ;

[0502] -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CO)-A-(CR 1a R 1b )1-5 -, where A is O, S or NR 1c ;or

[0503] -(CO)-(optionally with 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c .

[0504] In some embodiments of the compound of Formula IA-11 or Formula IA-12, each R 1a , each R 1b and each R 1c are independently H or C1-C6 alkyl.

[0505] In some embodiments of the compound of Formula IA-11 or Formula IA-12, R 1 For-(CR 1a R 1b ) 1-5 , such as, for example, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2- and the like.

[0506] In some embodiments of the compound of Formula IA-11 or Formula IA-12, R 1 For-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ), such as, for example, -CH2-O-, -CH2CH2-O-, -CH2CH2CH2-O-, and the like.

[0507] In some embodiments of the compound of Formula I, R 1 For-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -(where A is O, S or NR 1c ), such as, for example, -CH2CH2CH2-N(CH3)-CH2CH2-, -CH2CH2-N(CH3)-CH2CH2-, -CH2CH2-O-CH2-, and the like.

[0508] In some embodiments of the compound of Formula I, R 1 -(optionally replaced by 0-6 R 1aand / or R 1b substituted 3-11 membered heterocyclic group)-(CO)-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ), such as, for example, -piperidinyl-(CO)-CH(CH3)-O-, -pyrrolidinyl-(CO)-CH(CH3)-O-, -piperidinyl-(CO)-CH2-O-, -methylpiperidinyl-(CO)-CH2-O-, and the like.

[0509] In some embodiments of the compound of Formula I, R 1 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CO)-A-(CR 1a R 1b ) 1-5 -(where A is O, S or NR 1c ), such as, for example, -piperidinyl-(CO)-O-CH2-, and the like.

[0510] In some embodiments of the compound of Formula I, R 1 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ), such as, for example, -azabicyclo[3.1.1]heptyl-CH2CH2-O-, -azaspiro[3.3]heptyl-CH2CH2-O-, -piperidinyl-CH2CH2-O-, -fluoropiperidinyl-CH2CH2-O-, -azepanyl-CH2CH2-O-, -pyrrolidinyl-CH2CH2-O-, -piperidinyl-CH2CH(CH3)-O-, -octahydrocyclopenta[c]pyrrole -Hydroxy-CH2CH2-O-, -pyrrolidinyl-CH2CH(CH3)-O-, -methylpiperidinyl-CH2CH2-O-, -piperidinyl-CH2CH(CH2CH3)-O-, -pyrrolidinyl-CH2CH(CH2CH3)-O-, -pyrrolidinyl-CH2CH(CH3)-O-, -hydroxy-pyrrolidinyl-CH2CH2-O-, -hydroxy-piperidinyl-CH2CH2-O- and the like.

[0511] In some embodiments of the compound of Formula I, R 1 -(optionally replaced by 0-6 R 1a and / or R 1bsubstituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -, such as, for example, -piperidinyl-CH2-, -piperidinyl-CH2CH2-, -piperidinyl-CH2CH2CH2-, azetidinyl-CH2CH2CH2-, -aziridinyl-CH2-, -pyrrolidinyl-CH2CH2- and the like.

[0512] In some embodiments of the compound of Formula I, R 1 -(optionally replaced by 0-6 R 1a and / or R 1b 3-11 membered heterocyclic group substituted by a group)-(optionally substituted by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ), such as, for example, -piperidinyl-pyrrolidinyl-CH2CH2-O-, -piperidinyl-piperidinyl-CH2CH2-O-, -pyrrolidinyl-piperidinyl-CH2CH2-O-, and the like.

[0513] In some embodiments of the compound of Formula I, R 1 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ), such as, for example, -piperidinyl-CH2-piperidinyl-CH2CH2-O-, -piperidinyl-CH2CH2-piperidinyl-CH2CH2-O-, and the like.

[0514] In some embodiments of the compound of Formula I, R 1 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11-membered cycloalkyl)-A-(CR 1a R 1b ) 1-5 -(wherein each A is independently O, S or NR 1c), such as, for example, -cyclohexyl-N(CH3)-CH2CH2-O-, and the like.

[0515] In some embodiments of the compound of Formula I, R 1 -(CO)-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ), such as, for example, -(CO)-piperidinyl-CH2CH2-O-, and the like.

[0516] In some embodiments of the compound of Formula I, R 1 For-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -, such as, for example, -CH2-piperidinyl-CH2-, -CH2-piperidinyl-CH2CH2-, -CH2-piperidinyl-CH2CH2CH2- and the like.

[0517] In some embodiments of the compound of Formula I, R 1 For-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A- (wherein each A is independently O, S or NR 1c ), such as, for example, -CH2-pyrrolidinyl-CH2CH2-O-, -CH2-pyridinyl-CH2CH(CH3)-O-, -CH2-pyridinyl-CH2CH2-O-, -CH(CH3)-pyridinyl-CH2CH2-O-, -CH2-azepanyl-CH2CH(CH3)-O-, -CH2-azabicyclo[3.2.1]octyl-CH2CH2-O-, -CH2-(dimethyl)piperidinyl-CH2CH2-O-, -CH2dihydropiperidinyl-CH2CH2-O-, and the like.

[0518] In some embodiments of the compound of Formula I, R 1 For-(CR1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-A-(wherein A is O, S or NR 1c ), such as, for example, -CH2CH2CH2-pyrrolidinyl-O-, and the like.

[0519] In some embodiments of the compound of Formula I, R 1 -(optionally replaced by 0-4 R 1a and / or R 1b (substituted heteroaryl)-A-(CR 1a R 1b ) 1-5 -(where A is O, S or NR 1c ), such as, for example, -pyridinyl-O-CH2-, and the like.

[0520] In some embodiments of the compound of Formula I, R 1 -A-(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A- (wherein each A is independently O, S or NR 1c ), such as, for example, -N(CH3)-piperidinyl-CH2CH2-O-, and the like.

[0521] In some aspects, the compounds of Formula I are those having Formula IA-13a, IA-13b, IA-14a, or IA-14b:

[0522]

[0523]

[0524] wherein X is N or CH.

[0525] In some embodiments of compounds of Formula IA-13a, IA-13b, IA-14a, or IA-14b, R 1 -(optionally replaced by 0-6 R 1a and / or R 1b substituted 3-11 membered heterocyclic group)-(CO)-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ), or -(optionally replaced by 0-6 R 1a and / or R1b substituted 3-11 membered heterocyclic group)-(CR 1a R 1b ) 1-5 -A-(where A is O, S or NR 1c ),

[0526] R 1a 、R 1b 、R 1c and R 1e Each is independently -H, D, -halo, -C1-C8 alkyl, -C1-C6 haloalkyl, -O-C1-C8 alkyl, -S-C1-C8 alkyl, -NHC1-C8 alkyl, -N(C1-C8 alkyl)2, 3-11 membered cycloalkyl, aryl, heteroaryl, 3-11 membered heterocyclyl, -O-(3-11 membered cycloalkyl), -S-(3-11 membered cycloalkyl), NH-(3-11 membered cycloalkyl), N(3-11 membered cycloalkyl)2, N-(3-11 membered cycloalkyl)(C1-C8 alkyl), -OH, -NH 2, -SH, -SO2C1-C8 alkyl, SO(NH)C1-C8 alkyl, P(O)(OC1-C8 alkyl)(C1-C8 alkyl), -P(O)(OC1-C8 alkyl)2, -C≡C-C1-C8 alkyl, -C≡CH, -CH=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=C(C1-C8 alkyl)2, -Si(OH)3, -Si(C1-C8 alkyl)3, -Si(OH)(C1-C 8 alkyl)2, -C(O)C1-C8 alkyl, -CO2H, -CN, -CF3, -CHF2, -CH2F, -NO2, -SF5, -SO2NHC1-C8 alkyl, -SO2N(C1-C8 alkyl)2, -SO(NH)NHC1-C8 alkyl, -SO(NH)N(C1-C8 alkyl)2, -SONHC1-C8 alkyl, -SON(C1-C8 alkyl)2, -CONHC1-C8 alkyl, -CON(C1-C8 alkyl)2, -N(C1-C8 alkyl)CO NH(C1-C8 alkyl), -N(C1-C8 alkyl)CON(C1-C8 alkyl)2, -NHCONH(C1-C8 alkyl), -NHCON(C1-C8 alkyl)2, -NHCONH2, -N(C1-C8 alkyl)SO2NH(C1-C8 alkyl), -N(C1-C8 alkyl)SO2N(C1-C8 alkyl)2, -NHSO2NH(C1-C8 alkyl), -NHSO2N(C1-C8 alkyl)2, or -NHSO2NH2; or where the context permits, R 1a or R 1bconnected to other groups, or to each other, to form a group optionally with 0-4 R 1e The cycloalkyl and / or heterocyclyl moieties are substituted by radicals.

[0527] In some embodiments of compounds of Formula IA-13a, IA-13b, IA-14a, or IA-14b, R 1 -(3-11 membered heterocyclic)-(CO)-(CR 1a R 1b ) 1-3 -O-, where each R 1a For H and each R 1b is independently H or -C1-C8 alkyl, preferably -CH3.

[0528] In other embodiments of the compound of Formula IA-13a, IA-13b, IA-14a, or IA-14b, R 1 -(3-11 membered heterocyclic)-(CR 1a R 1b ) 1-3 -O-, where each R 1a For H and each R 1b is independently H or -C1-C8 alkyl, preferably -CH3.

[0529] In other embodiments of the compound of Formula IA-13a, IA-13b, IA-14a, or IA-14b, R 1 -azabicyclo[3.1.1]heptyl-CH2CH2-O-, -azaspiro[3.3]heptyl-CH2CH2-O-, -piperidinyl-CH2CH2-O-, -fluoropiperidinyl-CH2CH2-O-, -azepanyl-CH2CH2-O-, -pyrrolidinyl-CH2CH2-O-, -piperidinyl-CH2CH(CH3)-O-, -octahydrocyclopenta[c]pyrrolyl-C H2CH2-O-, -pyrrolidinyl-CH2CH(CH3)-O-, -methylpiperidinyl-CH2CH2-O-, -piperidinyl-CH2CH(CH2CH3)-O-, -pyrrolidinyl-CH2CH(CH2CH3)-O-, -pyrrolidinyl-CH2CH(CH3)-O-, -hydroxypyrrolidinyl-CH2CH2-O-, -hydroxypiperidinyl-CH2CH2-O-, and the like.

[0530] In some aspects, the compounds of Formula I are those having Formula IA-15a, IA-15b, IA-16a, or IA-16b:

[0531]

[0532]

[0533] Where A is O, S or NR 1c ,

[0534] R 1a1 is H or -C1-C8 alkyl, preferably -CH2CH3 or -CH3;

[0535] R 1c is -H or -C1-C8 alkyl, preferably -CH3;

[0536] A 1 For covalent bonds or -(CR 1a R 1b ) 1-3 ;and

[0537] Each R k H, D, F, C independently 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-4 Alkoxy, substituted C 1-3 Alkyl, substituted C 1-3 Haloalkyl or substituted C 1-4 alkoxy; and s=0-7.

[0538] In some embodiments of compounds of Formula IA-15a, IA-15b, IA-16a, or IA-16b, A is O and R 1a1 is -C1-C8 alkyl, preferably -CH2CH3 or -CH3.

[0539] In some embodiments of the compound of Formula IA-15a, IA-15b, IA-16a, or IA-16b, A 1 It is a covalent bond.

[0540] In some embodiments of the compound of Formula IA-15a, IA-15b, IA-16a, or IA-16b, A 1 For-(CR 1a R 1b ) 1-3 .

[0541] In some embodiments of compounds of Formula IA-15a, IA-15b, IA-16a, or IA-16b, A is O and R 1a1 is -CH3.

[0542] In some embodiments of the compound of Formula IA-15a, IA-15b, IA-16a, or IA-16b, s=0.

[0543] In some embodiments of compounds of Formula IA-15a, IA-15b, IA-16a, or IA-16b, s=1 and R k is -CH3.

[0544] In some embodiments, compounds of the present disclosure include:

[0545] (2S,4R)-4-hydroxy-1-((S)-2-(2-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0546] (2S,4R)-4-hydroxy-1-((S)-2-(2-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0547] (2S,4R)-4-hydroxy-1-((S)-2-(2-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)acetamido)-3,3-dimethylbutanoyl)-N-(4-(5-methylthiazol-4-yl)benzyl)pyrrolidine-2-carboxamide;

[0548] (2S,4R)-4-hydroxy-1-((S)-2-(2-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)acetamido)-3,3-dimethylbutanoyl)-N-(4-(5-methylthiazol-4-yl)benzyl)pyrrolidine-2-carboxamide;

[0549] (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-4-methylpiperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0550] (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0551] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0552] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0553] (2S,4R)-4-hydroxy-1-((S)-2-(3-(2-(4-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0554] (2S,4R)-4-hydroxy-1-((S)-2-(3-(2-(4-(((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0555] (2S,4R)-4-hydroxy-1-((S)-2-(4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)butanamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0556] (2S,4R)-4-hydroxy-1-((S)-2-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)butanamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0557] 2-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)ethyl((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate;

[0558] 2-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)ethyl((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate;

[0559] (2S,4R)-4-hydroxy-1-((S)-2-(3-(4-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propionamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0560] (2S,4R)-4-hydroxy-1-((S)-2-(3-(4-(((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propionamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0561] (3R,5S)-1-((R)-2-(3-(2-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl acetate;

[0562] (3R,5S)-1-((R)-2-(3-(2-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl acetate; (3R,5S)-1-((R)-2-(3-(2-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl isobutyrate;

[0563] (3R,5S)-1-((R)-2-(3-(2-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl isobutyrate;

[0564] (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0565] (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0566] (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(6-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-azabicyclo[3.1.1]hept-3-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0567] (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(6-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-azabicyclo[3.1.1]hept-3-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0568] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(6-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)-2-azaspiro[3.3]hept-2-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0569] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(6-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)-2-azaspiro[3.3]hept-2-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0570] (2S,4R)-4-hydroxy-1-((R)-2-(3-(((R)-1-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0571] (2S,4R)-4-hydroxy-1-((R)-2-(3-(((S)-1-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0572] (2S,4R)-4-hydroxy-1-((R)-2-(3-(((R)-1-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0573] (2S,4R)-4-hydroxy-1-((R)-2-(3-(((S)-1-(4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0574] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((S)-3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0575] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((R)-3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0576] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((S)-3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0577] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((R)-3-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0578] (2S,4R)-4-hydroxy-1-((R)-2-(3-(((S)-1-((S)-3-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0579] (2S,4R)-4-hydroxy-1-((R)-2-(3-(((S)-1-((S)-3-(((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0580] (2S,4R)-4-hydroxy-1-((R)-2-(3-(((S)-1-((R)-3-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0581] (2S,4R)-4-hydroxy-1-((R)-2-(3-(((S)-1-((R)-3-(((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0582] (2S,4R)-4-hydroxy-1-((R)-2-(3-(((R)-1-((S)-3-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0583] (2S,4R)-4-hydroxy-1-((R)-2-(3-(((R)-1-((S)-3-(((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0584] (2S,4R)-4-hydroxy-1-((R)-2-(3-(((R)-1-((R)-3-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0585] (2S,4R)-4-hydroxy-1-((R)-2-(3-(((R)-1-((R)-3-(((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0586] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((S)-3-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0587] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((R)-3-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0588] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((R)-3-(4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0589] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((S)-3-(4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0590] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((S)-3-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0591] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((S)-3-(4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0592] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((R)-3-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0593] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((R)-3-(4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0594] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3S,4R)-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)-2-oxoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0595] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3S,4S)-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)-2-oxoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0596] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3R,4R)-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)-2-oxoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0597] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3R,4S)-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)-2-oxoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0598] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3S,4R)-4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)-2-oxoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0599] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3R,4R)-4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)-2-oxoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0600] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3R,4S)-4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)-2-oxoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0601] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3S,4S)-4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)-2-oxoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0602] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((S)-3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0603] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((R)-3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0604] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((R)-3-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0605] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((S)-3-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0606] (2S,4R)-4-hydroxy-1-((R)-2-(3-(((S)-1-((R)-3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0607] (2S,4R)-4-hydroxy-1-((R)-2-(3-(((S)-1-((S)-3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0608] (2S,4R)-4-hydroxy-1-((R)-2-(3-(((S)-1-((S)-3-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0609] (2S,4R)-4-hydroxy-1-((R)-2-(3-(((S)-1-((R)-3-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0610] (2S,4R)-4-hydroxy-1-((R)-2-(3-(((R)-1-((R)-3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0611] (2S,4R)-4-hydroxy-1-((R)-2-(3-(((R)-1-((S)-3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0612] (2S,4R)-4-hydroxy-1-((R)-2-(3-(((R)-1-((S)-3-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0613] (2S,4R)-4-hydroxy-1-((R)-2-(3-(((R)-1-((R)-3-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0614] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((2R,4R)-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-2-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0615] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((2S,4R)-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-2-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0616] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((2R,4S)-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-2-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0617] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((2S,4S)-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-2-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0618] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((2R,4R)-4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-2-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0619] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((2S,4R)-4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-2-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0620] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((2R,4S)-4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-2-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0621] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((2S,4S)-4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-2-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0622] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3R,4S)-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0623] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3S,4R)-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0624] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3R,4R)-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0625] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3S,4S)-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0626] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3R,4S)-4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0627] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3S,4R)-4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0628] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3R,4R)-4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0629] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3S,4S)-4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0630] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-((S)-1-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)ethyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0631] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-((R)-1-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)ethyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0632] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-((S)-1-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)ethyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0633] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-((R)-1-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)ethyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0634] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-((R)-3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0635] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-((S)-3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0636] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-((S)-3-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0637] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-((R)-3-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0638] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((S)-3-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0639] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((R)-3-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0640] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((R)-3-(((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0641] (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((S)-3-(((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0642] (2S,4R)-4-hydroxy-1-((R)-2-(3-(3-((S)-3-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0643] (2S,4R)-4-hydroxy-1-((R)-2-(3-(3-((R)-3-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0644] (2S,4R)-4-hydroxy-1-((R)-2-(3-(3-((R)-3-(((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; or

[0645] (2S,4R)-4-Hydroxy-1-((R)-2-(3-(3-((S)-3-(((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0646] It is apparent that the compounds of the present invention (including all subgenera described herein) can have multiple stereocenters. Therefore, there are multiple stereoisomers (enantiomers and diastereomers) of the compounds (and subgenera described herein). The present disclosure contemplates and encompasses each stereoisomer of any compound encompassed by the present disclosure, as well as mixtures of such stereoisomers.

[0647] Pharmaceutically acceptable salts and solvates of the compounds of the present disclosure, including all subgenera described herein, are also within the scope of the present disclosure.

[0648] The present disclosure also contemplates isotopic variations of the compounds of the present disclosure, including all subgenera described herein.

[0649] Reference to Formula I or a subgenera thereof (e.g., Formula IA, IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9, IA-9a, IA-10, IA-10a, IA-11, IA-12, IA-13a, IA-13b, IA-14a, IA-14b, IA-15a, IA-15b, IA-16a, IA-16b) is intended to encompass the identified formula and all applicable subgenera.

[0650] It should be understood that, for the sake of clarity, certain features of the present invention described herein in the context of separate embodiments may also be provided in combination in a single embodiment. That is, unless clearly incompatible or expressly excluded, each separate embodiment is considered to be combinable with any other embodiment, and such combination is considered to be another embodiment. Conversely, for the sake of brevity, various features of the present invention described in the context of a single embodiment may also be provided individually or in any subcombination. Although an embodiment may be described as part of a series of steps or as part of a more general structure, each of the steps itself may also be considered an independent embodiment, which may be combined with other steps.

[0651] Pharmaceutical compositions and methods of administration

[0652] The subject pharmaceutical compositions are generally formulated to provide a therapeutically effective amount of a compound of the present disclosure as the active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. If desired, the pharmaceutical composition contains a pharmaceutically acceptable salt and / or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers and adjuvants.

[0653] The subject pharmaceutical composition can be used alone or in combination with one or more other medicaments, which are also usually used in the form of a pharmaceutical composition. Where desired, one or more compounds of the present invention and other medicaments can be mixed into a preparation, or two components can be formulated into separate preparations for use alone or in combination.

[0654] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions of the present invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.0 003%, 0.002%, 0.001%, 0.0009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% (or a number within a range bounded by and including any two of the above numbers) w / w, w / v or v / v.

[0655] In some embodiments, the concentration of one or more compounds of the invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14. .50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6 .25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04 %, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% (or a number within a range bounded by and including any two of the above numbers) w / w, w / v or v / v.

[0656] 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.

[0657] In some embodiments, the concentration of one or more compounds of the invention is in the range of about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w / w, w / v, or v / v.

[0658] 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. 1g, 0.09g, 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g or 0.0001g (or a number within a range bounded by and including any two of the above numbers).

[0659] 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, 0.0 035g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.0 08g, 0.0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.035g, 0.0 4g, 0.045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.095g, 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g, 0.5g, 0.55g, 0.6g, 0. 65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5, 3g, 3.5, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g or 10g (or a number within a range limited by and including any two of the above numbers).

[0660] In some embodiments, the amount of one or more compounds of the invention ranges from 0.0001 g-10 g, 0.0005 g-9 g, 0.001 g-8 g, 0.005 g-7 g, 0.01 g-6 g, 0.05 g-5 g, 0.1 g-4 g, 0.5 g-4 g, or 1 g-3 g.

[0661] The compound according to the present invention is effective over a wide dosage range. For example, in the treatment of adults, a dosage of 0.01 mg to 1000 mg, 0.5 mg to 100 mg, 1 mg to 50 mg, and 5 mg to 40 mg per day is an example of a dosage that can be used. An exemplary dosage is 10 mg to 30 mg per day. The exact dosage will depend on the route of administration, the form of administration of the compound, the subject to be treated, the subject's weight, and the attending physician's preference and experience.

[0662] The pharmaceutical compositions of the present invention generally contain the active ingredient of the present invention (e.g., a compound of the present disclosure) or a pharmaceutically acceptable salt and / or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including but not limited to inert solid diluents and fillers, diluents, sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers and adjuvants.

[0663] Non-limiting exemplary pharmaceutical compositions and methods for their preparation are described below.

[0664] Pharmaceutical compositions for oral administration .

[0665] In some embodiments, the present invention provides a pharmaceutical composition for oral administration comprising a compound of the present invention and a pharmaceutical excipient suitable for oral administration.

[0666] In some embodiments, the present invention provides a solid pharmaceutical composition for oral administration, comprising: (i) an effective amount of a compound of the present invention; optionally (ii) an effective amount of a second pharmaceutical agent; and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further comprises: (iv) an effective amount of a third pharmaceutical agent.

[0667] In some embodiments, the pharmaceutical composition can be a liquid pharmaceutical composition suitable for oral consumption. The pharmaceutical composition of the present invention suitable for oral administration can be presented in discrete dosage forms, such as capsules, cachets or tablets, or liquid or aerosol sprays, each of which contains a predetermined amount of active ingredient as a powder or granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such dosage forms can be prepared by any pharmaceutical method, but all methods include the step of associating the active ingredient with a carrier, which constitutes one or more essential ingredients. Typically, the composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then shaping the product into the desired appearance if necessary. For example, tablets can be prepared by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form such as a powder or granules in a suitable machine, the active ingredient optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent and / or a surfactant or dispersant. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0668] The present invention also encompasses anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, as water may promote the degradation of some compounds. For example, in the pharmaceutical field, water (e.g., 5%) can be added as a means of simulating long-term storage to determine the properties of the formulation over time, such as shelf life or stability. The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-moisture ingredients and low-moisture or low-humidity conditions. If it is expected that a large amount of contact with moisture and / or humidity will occur during manufacture, packaging, and / or storage, the pharmaceutical compositions and dosage forms of the present invention containing lactose can be made anhydrous. Anhydrous pharmaceutical compositions can be prepared and stored in a manner such that their anhydrous properties are maintained. Therefore, anhydrous compositions can be packaged using materials known to prevent exposure to water so that they can be included in suitable prescription kits. Examples of suitable packaging include, but are not limited to, sealed foils, plastics, etc., unit dose containers, blister packs, and strip packs.

[0669] According to conventional pharmaceutical compounding technology, active ingredient can be closely mixed with pharmaceutical carrier. The carrier can take various forms, depending on the form of preparation required for administration. When preparing the composition of oral dosage form, in the case of oral liquid preparations (such as suspensions, solutions and elixirs) or aerosols, any conventional pharmaceutical medium can be used as a carrier, such as water, glycol, oil, alcohol, flavoring, preservative, colorant, etc.; or in the case of oral solid preparations, in some embodiments without lactose, carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrants can be used. For example, in the case of solid oral preparations, suitable carriers include powders, capsules and tablets. If necessary, tablets can be coated by standard aqueous or non-aqueous technology.

[0670] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth gum, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

[0671] Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0672] Disintegrants can be used in the compositions of the present invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much disintegrant may produce tablets that may disintegrate in the bottle. Too little disintegrant may not be enough to disintegrate, and therefore may change the rate and extent of release of the active ingredient from the dosage form. Therefore, a sufficient amount of disintegrant (which will not adversely change the release of the active ingredient due to too little or too much) can be used to form the dosage form of the compound disclosed herein. The amount of disintegrant can vary according to the type of formulation and the mode of administration, and can be easily distinguished by those of ordinary skill in the art. About 0.5% by weight to about 15% by weight of disintegrant or about 1% by weight to about 5% by weight of disintegrant can be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algae, other celluloses, gums, or mixtures thereof.

[0673] The lubricant that can be used for forming pharmaceutical composition of the present invention and dosage form includes but is not limited to calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerine, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talcum, hydrogenated vegetable oil (for example, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar or their mixture.Other lubricant comprises the condensation aerosol of for example Syloid silica gel, synthetic silicon dioxide or their mixture.Lubricant can optionally add with the amount of about 1 % by weight less than pharmaceutical composition.

[0674] When aqueous suspensions and / or elixirs are required for oral administration, the active ingredient therein may be combined with various sweetening or flavoring agents, coloring agents or dyes and, if desired, emulsifying and / or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin, and various combinations thereof.

[0675] Tablets can be uncoated or can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a long period of time. For example, a time-delayed material such as glyceryl monostearate or glyceryl distearate can be used. Preparations for oral use can also be presented as hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules, wherein the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0676] Surfactants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants can be used, a mixture of lipophilic surfactants can be used, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant can be used.

[0677] Suitable hydrophilic surfactants can generally have an HLB value of at least 10, while suitable lipophilic surfactants can generally have an HLB value equal to or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values ​​are more lipophilic or hydrophobic and have greater solubility in oils, while surfactants with higher HLB values ​​are more hydrophilic and have greater solubility in aqueous solutions.

[0678] Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which HLB values ​​are generally not applicable. Similarly, lipophilic (e.g., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, the HLB value of a surfactant is only a rough guide that is commonly used to achieve the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0679] The hydrophilic surfactant can be an ionic or nonionic surfactant. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidates; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; phospholipids and their derivatives; lysolecithin and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; acyl lactylates; monoacetylated tartaric acid esters and diacetylated tartaric acid esters of monoglycerides and diglycerides; succinylated monoglycerides and diglycerides; citric acid esters of monoglycerides and diglycerides; and mixtures thereof.

[0680] Among the above-mentioned groups, ionic surfactants include, for example: lecithin, lysolecithin, phospholipids, lysophospholipids and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; acyl lactylates; monoacetylated tartaric acid esters and diacetylated tartaric acid esters of monoglycerides and diglycerides; succinylated monoglycerides and diglycerides; citric acid esters of monoglycerides and diglycerides; and mixtures thereof.

[0681] The ionic surfactant can be an ionized form of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactic acid esters of fatty acids, stearoyl-2-lactate, stearoyl lactylate, succinylated monoglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, citrate esters of mono / diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, myristyl sulfate, docusate, lauroylcarnitine, palmitoylcarnitine, myristoylcarnitine, and salts and mixtures thereof.

[0682] Hydrophilic nonionic surfactants may include, but are not limited to, alkyl glucosides; alkyl maltosides; alkyl thioglucosides; lauryl polyethylene glycol glycerides; polyoxyalkylene alkyl ethers, such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols, such as polyethylene glycol alkylphenols; polyoxyalkylene alkylphenol fatty acid esters, such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters, such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of polyols with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; polyoxyethylene sterols, derivatives and analogs thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of polyols with at least one member of the group consisting of triglycerides, vegetable oils and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or a sugar.

[0683] Other hydrophilic nonionic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 triolein, PEG-32 dioleate, PEG-20 laurin, PEG-30 laurin, PEG-20 stearin, PEG-20 olein, PEG-30 olein, PEG-30 laurin, PEG-40 laurin, PEG-40 palm kernel oil, PEG -50 Hydrogenated Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil, PEG-40 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Caprate / Caprylate Glycerides, PEG-8 Caprate / Caprylate Glycerides, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Phytosterols, PEG-30 Soybean Sterols, PEG-20 Trioleate, PEG-40 Dehydrogenated Castor Oil Sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopherol PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG15-100 octylphenol series and poloxamer.

[0684] By way of example only, suitable lipophilic surfactants include: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of monoglycerides and diglycerides; hydrophobic transesterification products of polyols with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins / vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters and mixtures thereof, or hydrophobic transesterification products of polyols with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils and triglycerides.

[0685] In one embodiment, the composition may include a solubilizing agent to ensure good solubilization and / or dissolution of the compound of the invention and to minimize precipitation of the compound of the invention. This is particularly important for compositions that are not used orally (e.g., compositions for injection). A solubilizing agent may also be added to increase the solubility of hydrophilic drugs and / or other components such as surfactants or to maintain the composition as a stable or uniform solution or dispersion.

[0686] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, diethylene glycol monoethyl ether, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; polyethylene glycol ethers having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycogen) or methoxy PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, glycerol triacetate, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers, β-butyrolactone and its isomers; and other solubilizers known in the art such as dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, glyceryl monocaprylate, diethylene glycol monoethyl ether and water.

[0687] Mixtures of solubilizing agents can also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methyl pyrrolidone, N-hydroxyethyl pyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, glycogen, diethylene glycol monoethyl ether, propylene glycol and dimethyl isosorbide. Particularly preferred solubilizing agents include sorbitol, glycerol, triacetin, ethanol, PEG-400, glycogen and propylene glycol.

[0688] The amount of the solubilizing agent that can be included is not particularly limited.The amount of a given solubilizing agent can be limited to the biologically acceptable amount that those skilled in the art can easily determine.In some cases, it may be advantageous to comprise the amount of the solubilizing agent that far exceeds the biologically acceptable amount, for example, so that the concentration of the medicine is maximized, wherein before providing compositions to the experimenter, conventional techniques (such as distillation or evaporation) are used to remove excessive solubilizing agent.Therefore, if present, based on the gross weight of medicine and other excipients, the weight ratio of solubilizing agent can be 10%, 25%, 50%, 100% or at the most about 200%> weight.If desired, a very small amount of solubilizing agent can also be used, such as 5%>, 2%>, 1% or even less.Usually, solubilizing agent can be by weight about 1%> to about 100%, more generally about 5%> to about 25%> amount exists.

[0689] The composition may further comprise one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, anti-adherents, defoaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity regulators, tonics, flavorings, colorants, flavor enhancers, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0690] In addition, acids or bases can be incorporated into the composition to facilitate processing, enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS), and the like. Also suitable are bases as salts of pharmaceutically acceptable acids, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkylsulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinonesulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc. Salts of polyacids can also be used, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, etc. Examples can include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0691] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkylsulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinonesulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid.

[0692] Pharmaceutical compositions for injection .

[0693] In some embodiments, the present invention provides a pharmaceutical composition for injection containing a compound of the present invention and a pharmaceutical excipient suitable for injection. The components and amounts of the pharmaceutical agents in the composition are as described herein.

[0694] Forms of the novel compositions of the present invention that may be incorporated for administration by injection include aqueous or oily suspensions or emulsions with sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, dextrose or sterile aqueous solutions and similar pharmaceutical vehicles.

[0695] Aqueous solutions in saline are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycols, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be used. Suitable fluidity can be maintained, for example, by using a coating such as lecithin to maintain the desired particle size in the case of dispersions and by using a surfactant. The action of microorganisms can be prevented by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0696] Sterile injectable solutions are prepared by incorporating the desired amount of the compound of the present invention into a suitable solvent along with various other ingredients as enumerated above, followed by filtration sterilization. Typically, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and other ingredients required from those enumerated above. Where sterile powders are used to prepare sterile injectable solutions, some desirable preparation methods are vacuum drying and freeze drying techniques, which produce a powder of the active ingredient plus any additional desired ingredients from its previously sterile filtered solution.

[0697] Pharmaceutical compositions for topical (eg, transdermal) delivery .

[0698] In some embodiments, the present invention provides a pharmaceutical composition for transdermal delivery comprising a compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery.

[0699] The compositions of the present invention can be formulated into solid, semisolid or liquid preparations suitable for topical or local application, such as gels, water-soluble gels, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, solutions based on dimethyl sulfoxide (DMSO). Generally speaking, carriers with higher densities can provide areas that are exposed to the active ingredient for a long time. In contrast, solution formulations can expose the active ingredient more directly to the selected area.

[0700] The pharmaceutical composition may also comprise suitable solid or gel phase carriers or excipients which are compounds that allow increased penetration of the therapeutic molecule across the stratum corneum permeability barrier of the skin or aid in the delivery of the therapeutic molecule. There are many such penetration enhancing molecules known to those trained in the art of topical formulations.

[0701] Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glyceryl monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0702] Another exemplary formulation for use in the methods of the present invention employs a transdermal delivery device ("patch"). Such transdermal patches can be used to provide continuous or discontinuous infusion of controlled amounts of a compound of the present invention, with or without another pharmaceutical agent.

[0703] The construction and use of transdermal patches for delivering pharmaceutical 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 configured for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

[0704] Pharmaceutical compositions for inhalation .

[0705] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the composition is administered via the oral or nasal respiratory route for local or systemic effect. Preferably, the composition in a pharmaceutically acceptable solvent can be aerosolized using an inert gas. The aerosolized solution can be inhaled directly from the aerosolizing device, or the aerosolizing device can be attached to a mask tampons or intermittent positive pressure breathing machine. The solution, suspension, or powder composition can be administered from a device that delivers the formulation in an appropriate manner, preferably orally or nasally.

[0706] Other pharmaceutical compositions .

[0707] Pharmaceutical compositions can also be prepared from the compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural or intraspinal administration. The preparation of such pharmaceutical compositions is well known in the art. , McGraw-Hill, 1999); all of these references are incorporated herein by reference in their entirety.

[0708] 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 routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, 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 intrafatally or intrathecally.

[0709] In some embodiments, the compounds or pharmaceutical compositions of the present invention are administered by intravenous injection.

[0710] The amount of the compound administered will depend on the severity of the subject being treated, obstacle or disease, rate of administration, the disposal of the compound and the judgment of the prescribing physician. However, effective dose is in the range of about 0.001mg / kg body weight / day to about 100mg / kg body weight / day, preferably in the range of about 1mg / kg / day to about 35mg / kg / day, with single dose or divided dose. For a 70kg person, this will be equivalent to about 0.05g / day to 7g / day, preferably about 0.05g / day to about 2.5g / day. In some cases, the dosage level below the above-mentioned lower limit of the range may be greater than enough dosage, and in other cases, larger dosage can be used without causing any harmful side effect, such as by being divided into several small dosages for full-day administration to such larger dosage.

[0711] In some embodiments, the compounds of the invention are administered in a single dose.

[0712] Typically, such administration will be by injection, for example intravenous injection, so as to rapidly introduce the agent. However, other routes may be used as appropriate. A single dose of a compound of the invention may also be used to treat acute conditions.

[0713] In some embodiments, the compounds of the present invention are administered in multiple doses. Administration can be about once, twice, three times, four times, five times, six times or more than six times a day. Administration can be about once a month, once every two weeks, once a week or once every other day. In another embodiment, the compounds of the present invention and another medicament are administered together about once a day to about 6 times a day. In another embodiment, the administration of the compounds of the present invention and the medicament continues for less than about 7 days. In another embodiment, administration continues for more than about 6 days, 10 days, 14 days, 28 days, two months, six months or one year. In some cases, continuous administration can be achieved and maintained as long as necessary.

[0714] The administration of the compounds of the present invention is continued as needed. In some embodiments, the administration of the compounds of the present invention is continued for more than 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days or 28 days. In some embodiments, the administration of the compounds of the present invention is continued for less than 28 days, 14 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day. In some embodiments, the compounds of the present invention are administered on an ongoing basis for a long term, for example, for the chronic effects of treatment.

[0715] An effective amount of the compounds of the present invention can be administered by any of the accepted modes of administration for similarly efficacious agents, including rectal, buccal, intranasal, and transdermal routes, by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant, in single or multiple doses.

[0716] The compositions of the present invention can also be delivered by, for example, impregnation or coating devices (such as, stents) or arterial insert cylindrical polymers. Such methods of administration 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 migration and proliferation of smooth muscle cells that cause restenosis in the arterial wall. The compounds of the present invention can, for example, be administered by local delivery from the struts of the stent, from stent grafts, from grafts, or from the covering or sheath of the stent. In some embodiments, the compounds of the present invention are mixed with a matrix. Such a matrix can be a polymer matrix and can be used to bind the compound to the stent. Polymer matrices suitable for such uses 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-based polymers or copolymers (e.g., polyhydroxyethyl methacrylate, polyvinyl pyrrolidone), fluorinated polymers such as polytetrafluoroethylene and cellulose esters. Suitable matrices can be non-degradable or can degrade over time, thereby releasing one or more compounds. The compounds of the present invention can be applied to the surface of the stent by various methods such as dip / spin coating, spray coating, dip coating and / or brush coating. The compound can be applied in a solvent and the solvent can be evaporated, thereby forming a compound layer on the stent. Alternatively, the compound can be located in the body of the stent or graft, for example, in a microchannel or micropore. 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 in a solution of the compound of the present invention in a suitable solvent and then evaporating the solvent. Excess drug on the stent surface can be removed by another short solvent wash. In other embodiments, the compound of the present invention can be covalently linked to the stent or graft. A covalent linker can be used that degrades in vivo, thereby releasing the compound of the present invention. Any biolabile bond such as an ester bond, an amide bond, or an anhydride bond can be used for such a purpose. In addition, the compound of the present invention can be administered intravascularly by the balloon used during angioplasty. Extravascular administration of the compound can also be performed by pericardial or adventitial application of the formulation of the present invention to reduce restenosis.

[0717] 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 5,451,233, U.S. Patent 5,040,548, U.S. Patent 5,061,273, U.S. Patent 5,496,346, U.S. Patent 5,292,331, U.S. Patent 5,674,278, U.S. Patent 3,657,744, U.S. Patent 4,739,762, U.S. Patent 5,195,984, U.S. Patent 5,292,331, U.S. Patent 5,674,278, U.S. Patent 5,879,382, U.S. Patent 6,344,053.

[0718] The compounds of the present invention can be administered in doses. It is known in the art that due to inter-subject variability in compound pharmacokinetics, individualization of the dosing regimen is necessary for optimal treatment. According to the present disclosure, the dosage of the compounds of the present invention can be determined by routine experimentation.

[0719] When a compound of the invention is administered in a composition containing one or more agents, and that agent has a shorter half-life than the compound of the invention, the unit dosage form of that agent and the compound of the invention may be adjusted accordingly.

[0720] The subject pharmaceutical composition can be, for example, in the form of a tablet, capsule, pill, powder, sustained-release formulation, solution, suspension suitable for oral administration, in the form of a sterile solution, suspension or emulsion suitable for parenteral injection, in the form of an ointment or cream suitable for topical administration, or in the form of a suppository suitable for rectal administration. The pharmaceutical composition can be a unit dosage form suitable for single administration of an exact dose. The pharmaceutical composition will comprise a conventional pharmaceutical carrier or excipient and a compound of the present invention as an active ingredient. In addition, it may comprise other drugs or medicaments, carriers, adjuvants, etc.

[0721] Exemplary parenteral administration forms include solutions or suspensions of the active compound in sterile aqueous solutions, for example, aqueous propylene glycol or glucose solution. Such dosage forms can be suitably buffered, if necessary.

[0722] How to use

[0723] The method generally includes administering a therapeutically effective amount of the compound of the present invention to the subject. The therapeutically effective amount of the subject combination of compound can be based on the intended application (in vitro or in vivo) or the subject and disease condition treated, such as the subject's weight and age, the severity of the disease condition, the mode of administration, etc. and change, which can be easily determined by those of ordinary skill in the art. The term is also applicable to the dosage that will induce a specific response (for example, the proliferation of the target protein is reduced or the activity is lowered) in the target cell. The specific dosage will vary according to the specific compound selected, the dosage regimen to be followed, whether to be administered in combination with other compounds, the time of administration, the tissue administered, and the physical delivery system that carries it.

[0724] In certain embodiments, the present invention provides pharmaceutical compositions comprising a compound of the bispecific formula or a pharmaceutically acceptable salt thereof.

[0725] In certain embodiments, the present invention provides pharmaceutical compositions comprising compounds of the bispecific formula for use in degrading a target protein in a cell.

[0726] In certain embodiments, the method of degrading a target protein comprises administering to a cell a therapeutically effective amount of a bispecific compound or a pharmaceutically acceptable salt thereof, wherein the compound is effective to degrade the target protein.

[0727] In certain embodiments, the present invention provides pharmaceutical compositions comprising compounds of the bispecific formula for use in treating or preventing diseases or disorders in which SMARCA2 and / or SMARCA4 play a role.

[0728] In certain embodiments, the present invention provides pharmaceutical compositions comprising compounds of the bispecific formula for use in treating or preventing diseases or disorders in which SWI / SNF mutations play a role.

[0729] In certain embodiments, the target protein is SMARCA2, SMARCA4, and / or PB1.

[0730] In certain embodiments, the target protein complex is SWI / SNF in a cell.

[0731] In certain embodiments, the disease or disorder dependent on SMARCA2 or SMARCA4 comprises cancer.

[0732] In certain embodiments, the disease or disorder dependent on the SWI / SNF complex comprises cancer.

[0733] Exemplary cancers that may be treated by the compounds of the present invention, alone or in combination with at least one additional anticancer agent, include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular and renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, and stomach cancer; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative disorders; sarcomas, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, , sarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma and schwannoma; intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratoma. Additional cancers that may 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, precursor B ALL, precursor B lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, and Philadelphia chromosome-positive CML.

[0734] In certain further embodiments, the cancer is a SMARCA2 and / or SMARAC4 dependent cancer.

[0735] In some embodiments, the cancer contains a SMARCA4 mutation.

[0736] In certain embodiments, the present invention provides pharmaceutical compositions comprising compounds of the bispecific formula for use in a disease or disorder dependent on SMARCA2 and / or SMARCA4, namely cancer.

[0737] The compounds of the present disclosure and pharmaceutical compositions comprising the same can be administered alone or in combination with medical therapies to treat any of the diseases. Medical therapies include, for example, surgery and radiotherapy (e.g., gamma rays, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, systemic radioisotopes).

[0738] In other aspects, the compounds of the present disclosure, and pharmaceutical compositions containing them, can be administered alone or in combination with one or more other agents to treat any of the described diseases.

[0739] In other methods, the compounds of the present disclosure, and pharmaceutical compositions containing them, can be administered in combination with agonists of nuclear receptor agents.

[0740] In other methods, the compounds of the present disclosure, and pharmaceutical compositions containing them, can be administered in combination with antagonists of nuclear receptor agents.

[0741] In other methods, the compounds of the present disclosure, and pharmaceutical compositions containing them, can be administered in combination with an anti-proliferative agent.

[0742] Combination therapy

[0743] In order to treat cancer and other proliferative diseases, the compound of the present invention can be used in combination with chemotherapeutic agents, agonists or antagonists of nuclear receptors or other antiproliferative agents. The compound of the present invention can also be used in combination with medical therapy, such as surgery or radiotherapy, for example, gamma radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy and systemic radioisotopes. The example of suitable chemotherapeutic agents includes any one of the following: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, all-trans retinoic acid, hexamethylmelamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bendamustine, bevacizumab, bexarotene, bleomycin. bortezombi, bortezomib, intravenous busulfan, oral busulfan, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium), dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin ozogamicin), goserelin acetate, histrelin acetate, ibritumomabtiuxetan), idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprorelin acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenylpropionate phenpropionate), nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab, panobinostat, pegaspargase, pegfilgrastim, pemetrexed disodium disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozotocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard mustard), valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.

[0744] In some embodiments, the compound of the present invention can be used in combination with the therapeutic agent of the targeting epigenetic regulator.The example of epigenetic regulator includes bromodomain inhibitors, histone lysine methyltransferase inhibitors, histone arginine methyltransferase inhibitors, histone demethylase inhibitors, histone deacetylase inhibitors, histone acetylase inhibitors and DNA methyltransferase inhibitors.Histone deacetylase inhibitors include, for example, vorinostat.Histone arginine methyltransferase inhibitors include inhibitors of protein arginine methyltransferase (PRMT) such as PRMT5, PRMT1 and PRMT4.DNA methyltransferase inhibitors include inhibitors of DNMT1 and DNMT3.

[0745] For the treatment of cancer and other proliferative diseases, the compounds of the present invention can be used in combination with targeted therapies, including JAK kinase inhibitors (e.g., ruxolitinib), PI3 kinase inhibitors (including PI3K-δ selective and broad-spectrum PI3K inhibitors), MEK inhibitors, cyclin-dependent kinase inhibitors (including CDK4 / 6 inhibitors and CDK9 inhibitors), BRAF inhibitors, mTOR inhibitors, proteasome inhibitors (e.g., bortezomib, carfilzomib), HDAC inhibitors (e.g., panobinostat, vorinostat), DNA methyltransferase inhibitors, dexamethasone, bromo- and extra-terminal family member (BET) inhibitors, BTK inhibitors (e.g., ibrutinib, acalabrutinib), BCL2 inhibitors (e.g., venetoclax), dual BCL2 family inhibitors (e.g., BCL2 / BCLxL), PARP inhibitors, FLT3 inhibitors, or LSD1 inhibitors.

[0746] 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.

[0747] 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).

[0748] Compounds of the present invention include, but are not limited to, those shown in Table 1.

[0749] Table 1.

[0750]

[0751]

[0752] Example

[0753] The compounds of the present invention can be prepared using the general procedures described below.

[0754] Plan A

[0755]

[0756] Compounds of formula (IA) can be synthesized using, for example, the sequence shown in Scheme A. Compounds A-1 and A-2 are linked via S N Ar reaction or Pd-catalyzed cross-coupling coupling gave compound A-3. Subsequent intramolecular S N Ar reaction or amide formation can provide the cyclized product A-4. Introducing a protecting group to promote Ar via, for example, Suzuki conditions (e.g., in the presence of a palladium catalyst such as, but not limited to, tetrakis(triphenylphosphine)palladium(0) or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane and a base (e.g., a carbonate base)) using an organometallic addition of an appropriate boronic acid or boronate ester or other Pd-catalyzed reaction to afford A-6. Using appropriate synthetic methods such as, but not limited to, S N 2 reaction, S N Ar reaction, reductive amination, Buchwald reaction, amide formation, Mitsunobu reaction, olefin metathesis, etc.) to introduce R 1 Compound A-7 can be obtained. The protecting groups on A-7 can be removed using standard conditions to give compound IA.

[0757] Plan I

[0758]

[0759] Compounds of formula I-8 can be synthesized using, for example, the sequence shown in Scheme 1. The S reaction between I-1 and compound I-2 in the presence of a base (e.g., Cs2CO3, NaHCO3, DIPEA) at elevated temperature is N The Ar reaction can provide alcohol I-3. Conversion of the hydroxyl group of I-3 to a leaving group (LG) under appropriate conditions (such as, but not limited to, treatment with SOCl2 or CBr4 / PPh3 or MsCl / Et3N) can provide compound I-4. Treatment of I-4 with NaN3 provides compound I-5. Reduction of the azide group of compound I-5 to the corresponding amine using PPh3 or Pd / H2, followed by intramolecular cyclization, provides compound I-6. Alternatively, compound I-4 can be treated with ammonium hydroxide at elevated temperatures to provide compound I-6. Protection of the -NH group with an appropriate group (e.g., Boc, SEM, Bn, etc.) can provide compound I-7, which can be converted to compound I-8 under standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as, but not limited to, tetrakis(triphenylphosphine)palladium(0) or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane and a base (e.g., a carbonate base)) using an appropriate boronic acid or boronic acid ester (e.g., 2-hydroxyphenylboronic acid).

[0760] Option II

[0761]

[0762] Compounds of formula II-5 can be synthesized using, for example, the sequence shown in Scheme II. N 2 reaction, reductive amination, etc.; for example, RG1 is a leaving group, such as bromide, and is replaced by the amine of II-1) and compound II-1 is coupled with R1 to obtain compound II-2. Suitable synthetic methods (such as but not limited to S N 2 reaction, S N Ar reaction, reductive amination, Buchwald reaction, amide formation, Mitsunobu reaction, olefin metathesis, etc.) are introduced into compound I-8 to obtain compound II-4. Alternatively, the synthesis of II-4 can be achieved by coupling I-8 with R1 and then introducing II-1 using the appropriate synthesis method described above. Removal of the protecting group can give a compound of formula II-5.

[0763] Option III

[0764]

[0765] Compounds of formula III-5 can be synthesized using, for example, the sequence shown in Scheme III. N 2 reaction, S N Ar reaction, Mitsunobu reaction, etc.) to couple compound III-1 with R1 to obtain compound III-2. Suitable synthesis methods (such as but not limited to S N 2 reaction, S N Ar reaction, reductive amination, Buchwald reaction, amide formation, Mitsunobu reaction, olefin metathesis, etc.) are introduced into compound I-8 to obtain compound III-4. Alternatively, the synthesis of III-4 can be achieved by coupling I-8 with R1 and then introducing intermediate III-1 using the appropriate synthesis method described above. Removal of the protecting group can give a compound of formula III-5.

[0766] Option IV

[0767]

[0768] Compounds of formula IV-4 can be synthesized using, for example, the sequence shown in Scheme IV. Coupling of compound IV-1 with an acid under standard amide coupling conditions (e.g., in the presence of a coupling agent such as HATU, HOBt, or PyBOP, treated with an appropriate base such as DIPEA or Et3N) affords amide IV-2. Nucleophilic addition of compound IV-3 under basic conditions (e.g., in the presence of a carbonate base, DIPEA, Et3N, etc.) affords compounds of formula IV-4.

[0769] Plan V

[0770]

[0771] An exemplary synthesis of compounds for preparing V-4 is described in Scheme V. Nucleophilic substitution of haloalkyl acids with compounds V-1 under basic conditions (e.g., in the presence of carbonate bases, DIPEA, Et3N, etc.) can provide ethers V-2. Coupling of amines IV-3 with carboxylic acids V-2 under standard amide coupling conditions (e.g., with an appropriate base such as DIPEA or trimethylamine and in the presence of coupling agents such as HATU, HOBt, or PyBOP) can provide amides V-3. Removal of protecting groups using appropriate conditions can provide compounds of formula V-4.

[0772] Plan VI

[0773]

[0774] An exemplary synthesis of compounds for preparing VI-3 is described in Scheme VI. Nucleophilic substitution of alkyl dihalides with alcohols V-1 under alkaline conditions (e.g., in the presence of carbonate bases, DIPEA, Et3N, etc.) can provide ethers VI-1. Nucleophilic substitution of VI-1 with amines IV-3 under alkaline conditions (e.g., in the presence of carbonate bases, DIPEA, Et3N, etc.) (wherein LG2 is a leaving group, such as a halo) can provide compounds VI-2. Removal of the protecting group under appropriate conditions can provide compounds of formula VI-3.

[0775] Scheme VII

[0776]

[0777] Compounds of formula VII-9 can be synthesized using, for example, the sequence shown in Scheme VII. Coupling of amine VII-1 with carboxylic acid VII-2 under standard amide coupling conditions (using an appropriate base such as, but not limited to, DIPEA or trimethylamine and in the presence of a coupling agent such as HATU, HOBt, or PyBOP) yields amide VII-3. Nucleophilic substitution of VII-3 with an alkyl dihalide under alkaline conditions (e.g., in the presence of a carbonate base, DIPEA, Et3N, etc.) yields compound VII-4. Nucleophilic substitution of VII-4 (wherein LG2 is a halo group) with IV-3 for the second time under alkaline conditions (e.g., in the presence of a carbonate base, DIPEA, Et3N, etc.) yields compound VII-5. Hydrolysis of the tert-butyl ester using appropriate conditions yields compound VII-6. Coupling of compound VII-6 with compound VII-7 under standard amide coupling conditions such as a base (e.g., DIPEA or trimethylamine) and in the presence of a coupling agent (e.g., HATU, HOBt, or PyBOP) yields amide VII-8. Deprotection of VII-8 can provide compounds of formula VII-9.

[0778] Scheme VIII

[0779]

[0780] Compounds of formula VIII-5 can be synthesized using, for example, the sequence shown in Scheme VIII. Reductive amination between compounds IV-3 and VIII-1 can provide compound VIII-2. Removal of the protecting group followed by nucleophilic substitution of VIII-4 (wherein LG is a halo) with VIII-3 under basic conditions (e.g., in the presence of a carbonate base, DIPEA, Et3N, etc.) can provide compounds of formula VIII-5.

[0781] Plan IX

[0782]

[0783] Compounds of formula IX-3 can be synthesized as shown in Scheme IX. Nucleophilic substitution of IX-1 (wherein LG is a halo) with VIII-3 under basic conditions (e.g., in the presence of a carbonate base, DIPEA, Et3N, etc.) can provide compound IX-2. Removal of the protecting group can provide compounds of formula IX-3.

[0784] Synthesis of intermediates

[0785] Intermediate 1: 2-(6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine- 2-aminophenyl)phenol (Int-1) .

[0786]

[0787] Step a. Synthesis of tert-butyl 4-(3,6-dichloropyridazin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (3) .

[0788] To a solution of pent-4-yn-1-ol (5.0 g, 59.4 mmol) and 3,4-dihydro-2H-pyran (10 g, 118 mmol) in DCM (10 mL) was added pyridine (9.6 mL, 118 mmol) and TsOH (22.6 g, 118 mmol) at 0 ° C. The mixture was stirred at 25 ° C for 16 h. The residue was washed with water (20 mL × 2) and then with saturated brine (20 mL). The organic matter was then separated and dried (MgSO4) and then concentrated to dryness. The crude product was then purified by silica gel column chromatography (100-200 mesh size, eluted with PE: EtOAc = 20: 1) to give tert-butyl 4- (3,6-dichloropyridazin-4-yl) -3- (hydroxymethyl) piperazine-1-carboxylate (3) (2.0 g, 11.8 mmol, 20% yield) as a white oil. 1 H NMR (DMSO, 400MHz): δ4.54-4.52(t,1H),3.75-3.71(m,2H),3.43-3.35(m,2H) ,2.72-2.71(t,1H),2.23-2.22(m,2H),1.70-1.59(m,4H),1.47-1.39(m,4H).

[0789] Step b. Synthesis of tert-butyl 3-(bromomethyl)-4-(3,6-dichloropyridazin-4-yl)piperazine-1-carboxylate (4) .

[0790] To a solution of N-bromosuccinimide (2.0 g, 11.3 mmol) and tert-butyl 4-(3,6-dichloropyridazin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (3) (4.1 g, 11.3 mmol) in DCM (50 mL) was added triphenylphosphine (5.9 mg, 22.6 mmol). The mixture was stirred at 25 ° C for 16 h. The mixture was washed with water (50 mL), concentrated in vacuo, and the residue was purified by silica gel chromatography (PE: EtOAc = 2: 1) to give tert-butyl 3-(bromomethyl)-4-(3,6-dichloropyridazin-4-yl)piperazine-1-carboxylate (4) (3.2 g, 7.5 mmol, 66.5% yield) as a white solid. 14 H 19 LCMS calculated for BrCl2N4O2: 426.1; found: LCMS [M+H]: 427.1.

[0791] Step c. Synthesis of tert-butyl 2-chloro-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (5): A mixture of tert-butyl 3-(bromomethyl)-4-(3,6-dichloropyridazin-4-yl)piperazine-1-carboxylate (4) (1.1 g, 2.6 mmol) in ammonium hydroxide solution (20 mL, 240 mmol) and 1,4-dioxane (20 mL) was stirred in an autoclave at 80° C. for 48 h. The reaction was concentrated in vacuo and the residue was purified by silica gel chromatography (SiO2, 200-300 mesh, PE:EtOAc = 1:2) to give tert-butyl 2-chloro-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (5) (330 mg, 1.0 mmol, 39% yield) as a white solid. 14 H 20 LCMS calculated for ClN5O2: 325.8; found: LCMS [M+H]: 326.2.

[0792] Step d. Synthesis of di-tert-butyl 2-chloro-6a,7,9,10-tetrahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate (6). To a solution of di-tert-butyl dicarbonate (401 mg, 1.8 mmol) and tert-butyl 2-chloro-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (5) (200 mg, 0.61 mmol) in DCM (5 mL) was added DMAP (62 mg, 0.61 mmol) and triethylamine (0.4 mL, 2.5 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The reaction was concentrated in vacuo and the residue was purified by silica gel chromatography (PE:EtOAc = 20:1 to 5:1) to give di-tert-butyl 2-chloro-6a,7,9,10-tetrahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate (6) (130 mg, 0.31 mmol, 50% yield) as a white solid. 19 H 28 LCMS calculated for ClN5O4: 425.9; found LCMS [M+H]: 426.3.

[0793] Step e. Synthesis of di-tert-butyl 2-(2-hydroxyphenyl)-6a,7,9,10-tetrahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate (8). To a solution of di-tert-butyl 2-chloro-6a,7,9,10-tetrahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate (6) (130 mg, 0.31 mmol) and 2-hydroxyphenylboronic acid (42 mg, 0.31 mmol) in 1,4-dioxane (5 mL) was added potassium carbonate (84.4 mg, 0.61 mmol) and Pd(dppf)2Cl2 (24.9 mg, 0.03 mmol) at room temperature. The mixture was stirred at 105°C for 18 h. The reaction was concentrated and the residue was purified by gel chromatography (SiO2, 200-300 mesh, PE:EtOAc = 1:2) to give di-tert-butyl 2-(2-hydroxyphenyl)-6a,7,9,10-tetrahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate (8) (180 mg, 0.41 mmol, 99.9% yield) as a white solid. 25 H 33 LCMS calculated for N5O5: 483.5; found: LCMS [M+H]: 484.3.

[0794] Step f. 2-(6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-2- Synthesis of 1,2-dimethyl-1,4-diol-2-ol (Int-1) .

[0795] A solution of di-tert-butyl 2-(2-hydroxyphenyl)-6a,7,9,10-tetrahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate (8) (180 mg, 0.37 mmol) in DCM (1.5 mL) and TFA (1.5 mL, 19.6 mmol) was stirred at 25°C for 2 h. The mixture was concentrated in vacuo, and the residue was added to 5 mL of water, adjusted to pH>7 with NaHCO3 (aq.), extracted with EtOAc, and filtered to give 2-(6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (Int-1) (70 mg, 0.24 mmol, 64% yield) as a white solid. 15 H 17 LCMS calculated for N5O: 283.3; found: LCMS [M+H]: 284.1. 1 H NMR(400MHz,DMSO-d6,)δ14.8(s,1H),7.91(s,1H),7.30(s,1H),7.19(s,2H),6.83-6.86(m,2H),3.92-3.94(m,1H) ,3.40-3.44(m,1H),3.13-3.15(m,2H),3.00-3.11(m,2H),2.66-2.76(m,2H),2.45-2.50(m,1H),2.28-2.33(m,1H).

[0796] 2-Chloro-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylic acid Alternative Synthesis of Tert-Butyl Ester (5) .

[0797]

[0798] Step a. Synthesis of tert-butyl 3-(azidomethyl)-4-(3,6-dichloropyridazin-4-yl)piperazine-1-carboxylate (15) .

[0799] To a solution of tert-butyl 3-(bromomethyl)-4-(3,6-dichloropyridazin-4-yl)piperazine-1-carboxylate (4) (2.7 g, 6.3 mmol) in DMF (15 mL) were added sodium azide (535 mg, 8.2 mmol) and 18-crown ether-6 (1.6 g, 6.3 mmol), and the mixture solution was stirred at 45 ° C for 18 h. Water (50 mL) and EtOAc (60 mL) were added to the mixture. Extracted with EtOAc (60 mL×2). The EtOAc layer was concentrated in vacuo to give tert-butyl 3-(azidomethyl)-4-(3,6-dichloropyridazin-4-yl)piperazine-1-carboxylate (15) (2.0 g, 5.2 mmol, 81% yield) as a yellow oil. 14 H 19 C l2 LCMS calculated value for N7O2: 387.1; found: LCMS [M+H]: 388.1.

[0800] Step b. 2-chloro-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine- Synthesis of tert-butyl 8-formate (5) .

[0801] To a solution of tert-butyl 3-(azidomethyl)-4-(3,6-dichloropyridazin-4-yl)piperazine-1-carboxylate (15) (2.0 g, 5.2 mmol) in DMF (10 mL) was added triphenylphosphine (1.4 g, 5.2 mmol) and the mixture was stirred at 45° C. for 18 h. The solution was added to a mixture of water (60 mL) and EtOAc (50 mL), extracted with EtOAc (60 mL×2), concentrated in vacuo, and the residue was purified by silica gel chromatography (SiO2, 200-300 mesh, PE:EtOAc 10:1 to 1:2) to give tert-butyl 2-chloro-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (5) (1500 mg, 4.6 mmol, 89% yield) as a yellow solid. 14 H 20 LCMS calculated for ClN5O2: 325.1; found: LCMS [M+H]: 326.2.

[0802] Intermediate 2. 2-((5-(1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1- (4-(4-methyl-1λ 3 ,3λ 2 -thiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxo (Int-2) .

[0803]

[0804] Step a. 2-((5-(1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1-(4- (4-methyl-1λ 3 ,3λ 2 -thiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2- Synthesis of ethyl)isoxazol-3-yl)oxy)acetate (10) .

[0805] At 25°C, (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methyl-1λ 3 ,3λ 2 To a solution of 2-((5-(1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1-(4-(4-methyl-1λ- methyl)-1-yl)-1-thiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (9) (prepared using the procedure described in US2020 / 0038378, 150 mg, 0.24 mmol) and ethyl 2-hydroxyacetate (51 mg, 0.48 mmol) in THF (15 mL) was added PPh3 (128 mg, 0.48 mmol) and DIAD (0.15 mL, 0.48 mmol), and the mixture was stirred at 25 ° C. for 2 h. The mixture was concentrated and the residue was purified by preparative TLC (PE:EtOAc=1:1) to give 2-((5-(1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1-(4-(4-methyl-1λ- methyl)-1-yl)-1-thiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (9) (prepared using the procedure described in US2020 / 0038378, 150 mg, 0.24 mmol) and ethyl 2-hydroxyacetate (51 mg, 0.48 mmol) in THF (15 mL) 3 ,3λ 2 1-thiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)ethyl acetate (10) (90 mg, 0.13 mmol, 53% yield) as a yellow oil. 35 H 50 LCMS calculated value for N4O7SSi: 698.32; found: LCMS [M+H]: 699.4.

[0806] Step b.2-((5-(1-((2 S ,4 R )-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1-(4- (4-methyl-1λ 3 ,3λ 2 -thiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2- Synthesis of 2-(4-(2-yl)isoxazol-3-yl)oxy)acetic acid (Int-2) .

[0807] 2-((5-(1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1-(4-(4-methyl-1λ 3 ,3λ 2A solution of ethyl acetate (10) (90 mg, 0.13 mmol) in a mixture of NaOH (10.2 mg, 0.3 mmol), water (6.0 mL) and methanol (12.0 mL) was stirred at 25° C. for 2 h. The mixture was adjusted to pH 4-5 by HCl (1N), extracted with EtOAc (40 mL×2), concentrated, and the residue was purified by preparative TLC (PE:EtOAc=1:1) to give 2-((5-(1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1-(4-(4-methyl-1λ)-1-yl)-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1-(4-(4-methyl-1λ)-1-yl)-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1-(4-(4-methyl-1λ)-1-yl)-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1-(4-(4-methyl-1λ)-1-yl)-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1-(4-(4-methyl-1λ)-1-yl)-4-((tert-butyldimethylsilyl)oxy)-2-(( 3 ,3λ 2 1-thiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)acetic acid (Int-2) (45 mg, 0.06 mmol, 52% yield) as a yellow oil. 33 H 46 LCMS calculated value for N4O7SSi: 670.29; found: LCMS [M+H]: 671.4.

[0808] Intermediate 3. (2S,4R)-1-(2-(3-(2-bromoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-(tert- (butyldimethylsilyl)oxy)-N-((S)-1-(4-(4-methyl-1λ 3 ,3λ 2 -thiazol-5-yl)phenyl)ethyl)pyrrole Alkane-2-carboxamide (Int-3) .

[0809]

[0810] At 25°C, (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methyl-1λ 3 ,3λ 2To a solution of 1,2-dibromoethane (45 mg, 0.24 mmol) in DMF (3 mL) was added NaHCO 3 (60 mg, 0.67 mmol) and 1,2-dibromoethane (5-(2-thiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (9) (prepared using the procedure described in US2020 / 0038378, 100 mg, 0.16 mmol) and 1,2-dibromoethane (45 mg, 0.24 mmol) was added NaHCO 3 (60 mg, 0.67 mmol) and the mixture was stirred at 30 ° C for 16 h. The reaction was dissolved in EtOAc (20 mL) and the organics were washed with water (20 mL×3) and brine (20 mL). The organics were then separated and dried (MgSO 4) and then concentrated to dryness. The product was then purified by preparative TLC (EtOAc:PE=2:1) ​​to give (2S,4R)-1-(2-(3-(2-bromoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(4-(4-methyl-1λ 3 ,3λ 2 -thiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Int-3) (50 mg, 0.07 mmol, 51% yield) as a sticky colorless solid. 33 H 47 LCMS calculated for BrN4O5SSi: 718.2; found: LCMS [M+H]: 719.3.

[0811] Intermediate 4. (2S,4R)-1-((R)-2-(3-(2-bromoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4- ((tert-Butyldimethylsilyl)oxy)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-yl Formamide (Int-4) .

[0812]

[0813] (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methyl-1λ 3 ,3λ 2 -thiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Int-3) was separated by preparative HPLC (eluting with 50% to 90% H2O:CH3CN (0.1% FA)) to give (2S,4R)-1-(2-(3-(2-bromoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(4-(4-methyl-1λ)-1-yl)-2-thiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Int-3) 3 ,3λ 2 -thiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (30 mg, 0.04 mmol, 25% yield) as a white solid. 33 H 47LCMS calculated for BrN4O5SSi: 718.2; found: LCMS [M+H]: 719.2.

[0814] Intermediate 5. (2S,4R)-1-((S)-2-(2-chloroacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N- (4-(4-methyl-1λ 3 ,3λ 2 -thiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-5) .

[0815]

[0816] (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methyl-1λ 3 ,3λ 2 To a solution of (2S,4R)-1-((S)-2-(2-chloroacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methyl-1λ-yl)-1-thiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (prepared using the procedure described in WO2018 / 0140809, 500 mg, 1.2 mmol) in DCM (15 mL) was added TEA (0.81 mL, 5.8 mmol), the reaction was cooled to 0°C, a solution of chloroacetyl chloride (262 mg, 2.3 mmol) in DCM (2 mL) was added, and the reaction was stirred at 25°C under N2 for 16 h. The reaction was washed with water (10 mL x 2), dried over Na2SO4, filtered and concentrated in vacuo, and the residue was purified by silica gel column chromatography (100-200 mesh size, eluted with DCM:MeOH = 25:1) to give (2S,4R)-1-((S)-2-(2-chloroacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methyl-1λ-yl)-1-thiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (prepared using the procedure described in WO2018 / 0140809, 500 mg, 1.2 mmol) in DCM (15 mL) 3 ,3λ 2 -thiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-5). (520 mg, 0.98 mmol, 84% yield) as a yellow solid. C 24 H 31 LCMS calculated value of ClN4O4S: 507.0; found: LCMS [m / z]: 507.2.

[0817] The intermediates in the following table were prepared by the method used to prepare Int-5:

[0818]

[0819]

[0820] Intermediate 8. 2-(8-(piperidin-4-ylmethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5] Pyrazino[2,3-c]pyridazin-2-yl)phenol (Int-8) .

[0821]

[0822] Step a. 4-((2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazine Synthesis of tert-butyl (2,3-c)pyridazin-8-yl)methyl)piperidine-1-carboxylate (16) .

[0823] To a solution of 1-Boc-piperidine-4-carbaldehyde (63.2 mg, 0.30 mmol) and 2-(6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (Int-1) (56 mg, 0.20 mmol) in DCM (10 mL) was added NaBH(OAc)3 (0.12 mL, 0.59 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo and purified by preparative TLC (MeOH:DCM=1:10) to give tert-butyl 4-((2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidine-1-carboxylate (16) (60 mg, 0.12 mmol, 63% yield) as a yellow solid. 26 H 36 LCMS calculated value of N6O3: 480.3; found value: LCMS [m / z] = 481.3.

[0824] Step b. 2-(8-(piperidin-4-ylmethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrrolidone Synthesis of 2-(2-methyl-1-oxazin-2-yl)phenol (Int-8) .

[0825] To a solution of tert-butyl 4-((2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidine-1-carboxylate (16) (60 mg, 0.12 mmol) in methanol (3 mL) was added HCl (0.07 mL, 0.37 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo to afford 2-(8-(piperidin-4-ylmethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (Int-8) (60 mg, 0.11 mmol, 91% yield) as a solid. 21 H 28 LCMS calculated value of N6O is 380.2; found value: LCMS [m / z] = 381.2.

[0826] The intermediates in the table below were prepared by the method used to prepare Int-8 using appropriate starting materials :

[0827]

[0828]

[0829]

[0830]

[0831]

[0832] Intermediate 9: (R)-2-(6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridinium Oxazin-2-yl)phenol (Int-9)

[0833]

[0834] Step 1: Synthesis of tert-butyl (R)-4-(3,6-dichloropyridazin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate

[0835]

[0836] To a solution of 3,4,6-trichloropyridazine (5.7 g, 31.1 mmol) in DMF (24 mL) was added N,N-diisopropylethylamine (5.9 mL, 34.2 mmol) and (R)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (7.1 g, 32.8 mmol). The reaction was stirred at 80 ° C overnight. The reaction was cooled to 45 ° C and water (17 mL) was slowly added. The resulting clear solution was stirred at 35 ° C for 30 min until a precipitate formed. Another portion of water (23 mL) was slowly added and the mixture was stirred at 0 ° C for another 1 h. The mixture was filtered and the resulting solid was washed with water and dried under vacuum to give (R)-tert-butyl 4-(3,6-dichloropyridazine-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (8.5 g, 75% yield) as an off-white solid. C 14 H 21 Cl2N4O3[M+H] + LCMS m / z calculated for: 363.1; found: 363.1.

[0837] Step 2: Synthesis of tert-butyl (R)-3-(azidomethyl)-4-(3,6-dichloropyridazin-4-yl)piperazine-1-carboxylate

[0838]

[0839] To a solution of (R)-4-(3,6-dichloropyridazin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (5.45 g, 15 mmol) and triphenylphosphine (4.7 g, 18 mmol) in THF (150 mL) was added diisopropyl azodicarboxylate (3.5 mL, 18 mmol) and DPPA (3.9 mL, 18 mmol) at 0 ° C. The reactants were then stirred at room temperature overnight. The reaction mixture was cooled to 0 ° C, quenched with water and extracted with EtOAc. The combined organic layers were washed with brine and water, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give crude (R)-3-(azidomethyl)-4-(3,6-dichloropyridazin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (19.4 g, 100% yield), which was used without further purification. Assuming 100% yield, 30% purity. C 14H 20 Cl2N7O2[M+H] + LCMS m / z calculated: 388.1; found: 388.0.

[0840] Step 3: (S)-2-chloro-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridinium Synthesis of tert-Butyl Oxazine-8-Carboxylate

[0841]

[0842] To a stirred solution of crude (R)-3-(azidomethyl)-4-(3,6-dichloropyridazin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (30% purity, 20.3 g, 15.7 mmol) in THF (200 mL) was added triphenylphosphine (4.9 g, 18.8 mmol). The resulting solution was stirred at 60 ° C for 3 h. Water (20 mL) and N, N-diisopropylethylamine (8.2 mL, 47.1 mmol) were added sequentially. After 20 h, the reaction mixture was diluted with EtOAc (100 mL) and water (100 mL). The aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0%-100% EtOAc / hexanes to afford (S)-tert-butyl 2-chloro-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (3.1 g, 60% yield) as an off-white solid. 14 H 21 ClN5O2[M+H] + LCMS m / z calculated: 326.1; found: 326.2.

[0843] Step 4: (R)-2-chloro-6a,7,9,10-tetrahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine- Synthesis of di-tert-butyl 5,8(6H)-dicarboxylate

[0844]

[0845] To a stirred solution of (S)-2-chloro-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylic acid tert-butyl ester (3.1 g, 9.5 mmol) in DCM (120 mL) was added di-tert-butyl dicarbonate (6.2 g, 28.6 mmol) and 4-(dimethylamino)pyridine (1.2 g, 9.5 mmol) at room temperature. After 1 h, the reaction was diluted with DCM (120 mL) and saturated NH4Cl aqueous solution (50 mL). After another 1 h, the aqueous layer was separated and extracted with DCM. The organic layers were combined, washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50% EtOAc / hexanes to give (R)-di-tert-butyl 2-chloro-6a,7,9,10-tetrahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate (3.9 g, 96% yield). 19 H 29 ClN5O4[M+H] + LCMS m / z calculated: 426.2; found: 426.3.

[0846] Step 5: (R)-2-(2-Hydroxyphenyl)-6a,7,9,10-tetrahydro-5H-pyrazino[1',2':4,5]pyrazino[2, Synthesis of di-tert-butyl 3-c]pyridazine-5,8(6H)-dicarboxylate

[0847]

[0848] To a solution of (R)-2-chloro-6a,7,9,10-tetrahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylic acid di-tert-butyl ester and 2-hydroxyphenylboronic acid (1.9 g, 14.1 mmol) in 1,4-dioxane (110 mL) was added potassium carbonate (3.89 g, 28.2 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (0.58 g, 0.70 mmol) at room temperature. The mixture was stirred at 105° C. for 18 h. The reaction was concentrated and the residue was purified by flash chromatography (SiO2, 200-300 mesh, EtOAc / hexane = 2 / 1) to give (R)-di-tert-butyl 2-(2-hydroxyphenyl)-6a,7,9,10-tetrahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate (2.6 g, 5.4 mmol, 76.% yield) as a white solid. 25 H 34 N5O5[M+H] + LCMS m / z calculated: 484.3; found: 484.3.

[0849] Step 6: (R)-2-(6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridinium Oxazine-2-yl ) Synthesis of phenol

[0850] To a stirred solution of (R)-2-(2-hydroxyphenyl)-6a,7,9,10-tetrahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylic acid di-tert-butyl ester (1.3 g, 2.7 mmol) in DCM (10 mL) was added 2,2,2-trifluoroacetic acid (4.1 mL) at room temperature. After 1 h, the reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in MeOH / DCM (1 / 6, 400 mL) and saturated NaHCO3 aqueous solution (80 mL) was added. The resulting mixture was stirred at 30 ° C for 30 min. The aqueous layer was separated and extracted with MeOH / DCM (1 / 6, 80 mL×4). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give crude (R)-2-(6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (700 mg, 92% yield) as a beige solid. 15 H 18 N5O[M+H] + LCMS m / z calculated: 284.2; found: 284.1. 1 H NMR(400MHz,DMSO-d6,)δ14.8(s,1H),7.91(s,1H),7.30(s,1H),7.19(s,2H),6.83-6.86(m,2H),3.92-3.94(m,1H) ,3.40-3.44(m,1H),3.13-3.15(m,2H),3.00-3.11(m,2H),2.66-2.76(m,2H),2.45-2.50(m,1H),2.28-2.33(m,1H).

[0851] Intermediate 9a. (S)-2-(6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c] Pyridazin-2-yl)phenol

[0852]

[0853] The title compound was prepared using procedures similar to those described for Int-9 using appropriate starting materials. 15 H 18 N5O[M+H] + LCMS m / z calculated: 284.2; found: 284.2.

[0854] Intermediate 12. (3R,5S)-1-((R)-2-(3-(2-bromoethoxy)isoxazol-5-yl)-3-methylbutanoyl)- 5-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl acetate

[0855]

[0856] Step 1: (2S,4R)-1-((R)-2-(3-(2-bromoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0857]

[0858] To a solution of (2S,4R)-1-((R)-2-(3-(2-bromoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Int-4) (100 mg, 0.14 mmol) in THF (5 mL) was added a THF solution of TBAF (0.1 mL, 7.3 mmol), and the mixture was stirred at room temperature for 2 h. The reaction was diluted with EA (20 mL) and washed with brine (30 mL x 2). The organic layer was concentrated to give the product, which was used in the next step without further purification. 27 H 34 BrN4O5S[M+H] + LCMS m / z calculated for: 605.1; found: 605.1.

[0859] Step 2: (3R,5S)-1-((R)-2-(3-(2-bromoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5- (((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl acetate

[0860] To a solution of (2S,4R)-1-((R)-2-(3-(2-bromoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (45 mg, 0.07 mmol) in DCM (5 mL) was added DMAP (48.0 mg, 0.37 mmol) and acetic anhydride (37.9 mg, 0.37 mmol), and the mixture solution was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc (20 mL) and the organic layer was washed with water (2×10 mL) and then saturated brine (1×10 mL). The organic layer was separated, dried over MgSO 4 , and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (PE:EA=1:1) to give (3R,5S)-1-((R)-2-(3-(2-bromoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl acetate (40 mg, 0.06 mmol, 83% yield). 29 H 36BrN4O6S[M+H] + LCMS m / z calculated value: 647.1; found value: 647.1

[0861] Intermediate 13. (3R,5S)-1-((R)-2-(3-(2-bromoethoxy)isoxazol-5-yl)-3-methylbutanoyl)- 5-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl isobutyrate

[0862]

[0863] The title compound was prepared using procedures analogous to those described for Int-12, substituting isobutyric anhydride for acetic anhydride in step 2. 31 H 40 BrN4O6S[M+H] + LCMS m / z calculated: 675.2; found: 675.2.

[0864] Intermediate 19. 2-((6aS)-8-(pyrrolidin-3-yl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2': 4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (diastereomer 1)

[0865]

[0866] Step 1: 3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5] ... 8-Zinco[2,3-c]pyridazinyl ) Tert-Butyl pyrrolidine-1-carboxylate (mixture of 2 diastereomers)

[0867]

[0868] The title compound was prepared using procedures similar to those described for Int-8 step a with appropriate starting materials. 24 H 33 N6O3[M+H] + LCMS m / z calculated: 453.3; found: 453.3.

[0869] Step 2: 3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5] ... tert-Butyl (2,3-c]pyridazin-8-yl)pyrrolidine-1-carboxylate (Diastereomer 1)

[0870]

[0871] 46.8 g of tert-butyl 3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidine-1-carboxylate (mixture of 2 diastereomers) were purified on chiral supercritical fluid chromatography using the following conditions: Column: OJ (250*25mm 10mm); mobile phase: 50% EtOH / CO2; pressure: 100 bar; flow rate: 70g / min; UV: 214nM; injection: 3.0mL, 58.5mg / mL MeOH solution. 22g of tert-butyl 3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidine-1-carboxylate (diastereomer 1, t r =3.0min). C 24 H 33 N6O3[M+H] + LCMS m / z calculated value: 453.3; found value: 453.2. 18 g of tert-butyl 3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidine-1-carboxylate (diastereomer 2, t r =4.5min). C 24 H 33 N6O3[M+H] + LCMS m / z calculated: 453.3; found: 453.3.

[0872] Step 3: 2-((6aS)-8-(pyrrolidin-3-yl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4, 5]Pyrazino[2,3-c]pyridazin-2-yl)phenol (diastereomer 1)

[0873] To a stirred solution of tert-butyl 3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidine-1-carboxylate (diastereomer 1, 2.0 g, 4.4 mmol) in DCM (10 mL) was added TFA (1.0 mL) at room temperature. After 16 h, the volatiles were removed under reduced pressure and the residue was used in the next step without further purification. 19 H 25 N6O[M+H] + LCMS m / z calculated: 353.2; found: 353.0.

[0874] Intermediate 20. 2-((6aS)-8-(pyrrolidin-3-yl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2': 4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (diastereomer 2)

[0875]

[0876] To a stirred solution of tert-butyl 3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidine-1-carboxylate (2 diastereomers from step 2 of the synthesis of Int-19, 2.0 g, 4.42 mmol) in DCM (10 mL) was added TFA (1 mL) at room temperature. After 16 h, the volatiles were removed under reduced pressure and the residue was used in the next step without further purification. 19 H 25 N6O[M+H] + LCMS m / z calculated: 353.2; found: 353.1.

[0877] Intermediate 23. (S)-2-(8-(1-(2-(piperazin-1-yl)ethyl)piperidin-4-yl)-6,6a,7,8,9,10-hexa 5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol

[0878]

[0879] Step 1: (S)-4-(2-(4-(2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2': tert-Butyl 4,5-pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethyl)piperazine-1-carboxylate

[0880]

[0881] To a solution of Int-11 (30 mg, 0.08 mmol) and tert-butyl 4-(2-bromoethyl)piperazine-1-carboxylate (40 mg, 0.14 mmol) in DMF (30 mL) was added NaHCO 3 (13.8 mg, 0.40 mmol) at room temperature. The mixture was stirred at 65 ° C for 48 h. The reaction mixture was concentrated and purified by preparative TLC (MeOH: DCM = 1: 10) to give (S) -4- (2- (4- (2- (2-hydroxyphenyl) -5,6,6a,7,9,10-hexahydro -8H- pyrazino [1 ', 2 ': 4,5] pyrazino [2,3-c] pyridazin-8-yl) piperidin-1-yl) ethyl) piperazine-1-carboxylate (40 mg, 0.069 mmol, 84% yield) as a yellow solid. 31 H 47 N8O3[M+H] + LCMS m / z calculated: 579.4; found: 579.2.

[0882] Step 2: (S)-2-(8-(1-(2-(piperazin-1-yl)ethyl)piperidin-4-yl)-6,6a,7,8,9,10-hexahydro- 5H-Pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol

[0883] To a solution of (S)-tert-butyl 4-(2-(4-(2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethyl)piperazine-1-carboxylate (40 mg, 0.07 mmol) in DCM (1 mL) was added TFA (0.03 mL, 0.16 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. The volatiles were removed in vacuo and the residue was used in the next step without further purification. 26 H 39 N8O[M+H] + LCMS m / z calculated: 479.3; found: 479.2.

[0884] Intermediate 24. (S)-2-(8-(1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)-6,6a,7,8,9,10-hexa 5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol

[0885]

[0886] Step 1: (S)-4-(2-(4-(2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2': tert-Butyl 4,5-pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethyl)piperidine-1-carboxylate

[0887]

[0888] To a solution of Int-11 (30.0 mg, 0.08 mmol) and tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (27.91 mg, 0.12 mmol) in DCM (30 mL) was added NaBH(OAc)3 (34 mg, 0.16 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. The volatiles were removed in vacuo and the residue was purified by preparative TLC (MeOH:DCM=1:10) to give (S)-tert-butyl 4-(2-(4-(2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethyl)piperidine-1-carboxylate (30.0 mg, 0.051 mmol, 63.4% yield) as a yellow solid. 32 H 48 N7O3[M+H] + LCMS m / z calculated: 578.4; found: 578.1.

[0889] Step 2: (S)-2-(8-(1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)-6,6a,7,8,9,10-hexahydro- 5H-Pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol

[0890] To a solution of (S)-tert-butyl 4-(2-(4-(2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethyl)piperidine-1-carboxylate (40.0 mg, 0.07 mmol) in DCM (30 mL) was added TFA (0.3 mL) at room temperature. The mixture was stirred at room temperature for 16 h. LCMS showed that the reaction was complete. The volatiles were removed in vacuo and the residue was used in the next step without further purification. 27 H 40 N7O[M+H] + LCMS m / z calculated: 478.3; found: 478.2.

[0891] Intermediate 27. (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((R)-2-(3-hydroxyisothiazolinone (4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0892]

[0893] 23 g of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide were purified on chiral supercritical fluid chromatography using the following conditions: Column: DAICEL Whelk (250*25mm10mm); mobile phase: 50% IPA / CO2; pressure: 100 bar; flow rate: 70g / min; UV: 214nM; injection: 2.5mL, 76.7mg / mL MeOH solution. 10.7g (peak 1, t r =5.0min)(2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((R)-2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide. C 31 H 45 N4O5SSi[M+H] + LCMS m / z calculated: 613.3; found: 613.3.

[0894] Intermediate 28. (S)-2-((5-((R)-1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2- (((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxo (butyl-2-yl)isoxazol-3-yl)oxy)propanoic acid

[0895]

[0896] Step 1: (S)-2-((5-((R)-1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2- (((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxo Methyl butyl-2-ylisoxazol-3-yloxypropanoate

[0897]

[0898] To a stirred mixture of (2R)-methyl 2-hydroxypropanoate (67.9 mg, 0.65 mmol), (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((R)-2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (200 mg, 0.33 mmol) and PPh (171 mg, 0.65 mmol) in THF (10 mL) was added DIAD (0.12 mL, 0.65 mmol) at 0° C. After 1 h, the reaction mixture was warmed to room temperature. After an additional 16 h, the volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (eluting with CH3CN in H2O: (0.1% NH4HCO3) 10% to 95%) to give (S)-methyl 2-((5-((R)-1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)propanoate (180 mg, 0.25 mmol, 77.3% yield) as a white solid. C 35 H 51 N4O7SSi[M+H] + LCMS m / z calculated: 699.3; found: 699.3.

[0899] Step 2 :(S)-2-((5-((R)-1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)propanoic acid

[0900] A mixture of LiOH (31 mg, 1.29 mmol) and (S)-2-((5-((R)-1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)propanoate (180 mg, 0.26 mmol) in THF (5 mL) and water (5 mL) was stirred at 0 °C for 2 h. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (eluting with CH3CN in H2O: (0.1% NH4HCO3) 10% to 95%) to give (S)-2-((5-((R)-1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)propanoic acid (150 mg, 0.21 mmol, 83.4% yield) as a white solid. C 34 H 49 N4O7SSi[M+H] + LCMS m / z calculated: 685.3; found: 685.3.

[0901] Intermediate 31.2-(6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2, 3-c]pyridazin-2-yl)phenol

[0902]

[0903] Step 1: 1,4-di-tert-butyl 2-methylpiperazine-1,2,4-tricarboxylate

[0904]

[0905] To a solution of 1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (5.0 g, 15.1 mmol) and potassium carbonate (4.18 g, 30.3 mmol) in acetone (50 mL) was added iodomethane (2.17 g, 15.3 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in EA (100 mL) and washed with brine (100 mL×2). The organic layer was concentrated in vacuo to give 1,4-di-tert-butyl 2-methylpiperazine-1,2,4-tricarboxylate (5.2 g, 15.1 mmol, 99.7% yield) as a white solid. C 16 H 29 N2O6[M+H] + LCMS calculated value: 345.2; found value: 345.2.

[0906] Step 2: 1,4-di-tert-butyl 2-methylpiperazine-1,2,4-tricarboxylate

[0907]

[0908] To a solution of 1,4-di-tert-butyl 2-methyl piperazine-1,2,4-tricarboxylate (5.2 g, 15.1 mmol) in THF (100 mL) was added LiHMDS (2.8 g, 16.6 mmol) at -78 ° C. The mixture was stirred at -78 ° C for 2 h, and then iodomethane (6.4 g, 45.3 mmol) was added at -78 ° C. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with saturated NH4Cl aqueous solution (100 ml) at 0 ° C, diluted with EA (200 ml), and washed with water (2 × 100 mL) and then brine (50 ml). The organic layer was dried (MgSO4), filtered, and the filtrate was concentrated to dryness. The crude product was purified by silica gel column chromatography (100-200 mesh size) using PE:EA = 3:1 to 1:1 as eluent to give 1,4-di-tert-butyl 2-methylpiperazine-1,2,4-tricarboxylate (5.0 g, 13.9 mmol, 91.4% yield) as a yellow oil. 17 H 31 N2O6[M+H] + LCMS calculated value: 359.2; found: 359.3.

[0909] Step 3: 1,4-bis(tert-butoxycarbonyl)-2-methylpiperazine-2-carboxylic acid

[0910]

[0911] To a solution of 1,4-di-tert-butyl 2-methylpiperazine-1,2,4-tricarboxylate (5.0 g, 13.9 mmol) in THF (12 mL) / methanol (2 mL) / water (2 mL) was added LiOH (713 mg, 17.0 mmol). The mixture was stirred at 50 ° C for 16 h. TLC showed that the reaction was complete. The reaction mixture was washed with PE (100 mL × 2). The pH of the aqueous layer was adjusted to 3-4 with 1N HCl and then extracted with EA (100 mL × 3). The organic layers were combined, washed with brine (50 mL), and concentrated under reduced pressure to give the product 1,4-bis (tert-butoxycarbonyl) -2-methylpiperazine-2-carboxylic acid (4.5 g, 13.1 mmol, 93.7% yield) as a white solid. C 16 H 29 N2O6[M+H] + LCMS calculated value: 345.2; found value: 345.2.

[0912] Step 4: 2-Chloro-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazine tert-Butyl 2,3-daprazine-8-carboxylate

[0913]

[0914] To a solution of 1,4-bis(tert-butoxycarbonyl)-2-methylpiperazine-2-carboxylic acid (4.2 g, 12.2 mmol) in DCM (25 mL) was added DMF (1 mL) and oxalyl chloride (4.6 g, 36.6 mmol). The mixture was stirred at room temperature for 30 min. The volatiles were removed under reduced pressure and DMF (25 mL), DIEA (10.1 mL, 61.0 mmol) and 5-bromo-6-chloropyridazine-3-amine (5.1 g, 24.4 mmol) were added sequentially. The resulting mixture was stirred at 120 ° C for 16 h. The reaction mixture was diluted with EA (100 mL) and washed with brine (30 mL × 2). The organic layer was concentrated in vacuo and purified by preparative TLC using PE:EA=1:1 as eluent to give tert-butyl 2-chloro-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (1.5 g, 4.2 mmol, 34.7% yield) as a yellow solid. 15 H 21 ClN5O3[M+H] + LCMS calculated value: 354.1; found: 354.1.

[0915] Step 5 : 2-Chloro-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3- c] tert-Butyl pyridazine-8-carboxylate

[0916]

[0917] To a solution of tert-butyl 2-chloro-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (87.3 mg, 0.25 mmol) in THF (8 mL) was added a solution of BH3 in THF (1 M, 0.74 mL, 0.74 mmol). The resulting mixture was stirred at 80 ° C for 16 h. The reaction was diluted with MeOH (20 mL) and stirred at 80 ° C for another 16 h. The volatiles were removed under reduced pressure and the residue was purified by preparative TLC (DCM:MeOH=10:1) to give tert-butyl 2-chloro-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (40.0 mg, 0.12 mmol, 47.7% yield) as a yellow solid. 15 H 23 ClN5O2[M+H] +LCMS calculated value: 340.2; found value: 340.1

[0918] Step 6: 2-(2-Hydroxyphenyl)-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5] tert-Butyl pyrazino[2,3-c]pyridazine-8-carboxylate

[0919]

[0920] To a solution of 2-hydroxyphenylboronic acid (731 mg, 5.3 mmol), potassium carbonate (1.1 g, 7.95 mmol) and tert-butyl 2-chloro-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (900 mg, 2.65 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added Pd(dppf)Cl (216 mg, 0.26 mmol). The mixture was stirred at 105 ° C under N for 16 h. The reaction was diluted with EA (200 mL) and washed with brine (100 mL×2). The organic layer was concentrated and the residue was purified by silica gel column chromatography (100-200 mesh size) eluting with PE:EA = 3:1 to 1:1 to give tert-butyl 2-(2-hydroxyphenyl)-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (1.0 g, 2.51 mmol, 95.0% yield) as a yellow solid. 21 H 28 N5O3[M+H] + LCMS calculated value: 398.2; found: 398.2.

[0921] Step 7: 2-(6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c] Pyridazin-2-yl)phenol

[0922] To a solution of tert-butyl 2-(2-hydroxyphenyl)-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate (60.0 mg, 0.15 mmol) in DCM (1 mL) was added TFA (1.2 mL). The mixture was stirred at 25 ° C for 2 h. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC, eluting with 5.0% to 95% CH 3 CN in HO (0.1% HCl) to give 2-(6a-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol as its HCl salt (45.0 mg, 0.13 mmol, 87.9% yield). 1H NMR (400MHz, CD3OD) δ7.54-7.52(m,1H),7.45-7.41(m,1H),7.26(s,1H),7.06-7. 01(m,2H),4.26-4.22(m,1H),3.65-3.44(m,5H),3.24-3.12(m,2H),1.55(m,3H). C 16 H 20 N5O[M+H] + LCMS calculated value: 298.2; found: 298.2.

[0923] Intermediate 32: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-formylisoxazole-5- 1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0924]

[0925] Step 1: 2-(Benzyloxy)acetaldehyde

[0926]

[0927] To a solution of 2-(benzyloxy)ethane-1-ol (1.0 g, 6.6 mmol) in MeCN (30 mL) was added IBX (8.4 g, 19.7 mmol). The mixture was stirred at 90 ° C for 10 min. The reaction was diluted with EtOAc (30 mL) and washed with water (2 × 10 mL) and then saturated brine (1 × 10 mL). The organic layer was dried over MgSO4, filtered and concentrated to dryness. The crude product was then purified by silica gel chromatography (EA: PE = 1: 5) to give 2-(benzyloxy)acetaldehyde (150 mg, 1.00 mmol). C9H 11 O2[M+H] + LCMS calculated value: 151.1; found: 151.1.

[0928] Step 2: (E)-2-(Benzyloxy)acetaldehyde oxime

[0929]

[0930] To a solution of 2-(benzyloxy)acetaldehyde (1.0 g, 6.7 mmol) and hydroxylamine hydrochloride (508 mg, 7.33 mmol) in ethanol (10 mL) and water (30 mL) was added NaOH (666 mg, 16.6 mmol) at 0 ° C. The reaction was stirred at 0 ° C for 2 h. The resulting mixture was acidified to pH 2 with HCl (5N). The mixture was extracted with EA (30 mL×2). The combined organic layers were washed with brine (8.0 mL), dried over MgSO4 and concentrated to give (E)-2-(benzyloxy)acetaldehyde oxime (500 mg, 3.0 mmol, 44.5% yield) as a colorless oil. C9H 12 NO2[M+H] + LCMS calculated value: 166.1; found: 166.1.

[0931] Step 3: (Z)-2-(Benzyloxy)-N-hydroxyacetimidoyl chloride

[0932]

[0933] To a solution of (E) -2- (benzyloxy) acetaldehyde oxime (500 mg, 3.0 mmol) in DMF (10 mL) was added NCS (808 mg, 6.0 mmol). The reaction was stirred at 90 ° C for 2 h. The resulting mixture was diluted with EA (50 mL) and washed with water (2 × 30 mL) and saturated brine (1 × 10 mL). The organic layer was dried over MgSO4 and concentrated to dryness. The residue was purified by silica gel chromatography (PE: EA = 8: 1) to give (Z) -2- (benzyloxy) -N- hydroxyacetimidoyl chloride (603 mg, 2.96 mmol, 97.8% yield) as a colorless oil. 1 H-NMR (CD3OD-d4, 400MHz): δ12.080(s,1H),7.324-7.369(m,5H),4.492(s,2H),4.262(s,2H).

[0934] Step 4: 2-(3-((Benzyloxy)methyl)isoxazol-5-yl)ethan-1-ol

[0935]

[0936] To a solution of (Z)-2-(benzyloxy)-N-hydroxyacetimidoyl chloride (6.4 g, 32.1 mmol) and NaHCO3 (3.4 g, 40.1 mmol) in EA (20 mL) and water (20 mL) was added 3-butyn-1-ol (2.76 g, 39.4 mmol). The reaction was stirred at 25 ° C for 2 h. The resulting mixture was diluted with EA (50 mL) and then washed with water (2×30 mL) and brine (1×10 mL). The organic layer was dried over MgSO4 and concentrated to dryness. The residue was purified by silica gel chromatography (PE:EA=1:1) to give 2-(3-((benzyloxy)methyl)isoxazol-5-yl)ethan-1-ol (2.7 g, 11.6 mmol, 36.1% yield) as an oil. C 13 H 16 NO3[M+H] + LCMS calculated value: 234.1; found: 234.0.

[0937] Step 5: 2-(3-((Benzyloxy)methyl)isoxazol-5-yl)acetic acid

[0938]

[0939] To a solution of 2-(3-((benzyloxy)methyl)isoxazol-5-yl)ethan-1-ol (100 mg, 0.43 mmol) in water (0.20 mL) and acetone (2 mL) was added chromium (III) oxide (65.2 mg, 0.43 mmol) and sulfuric acid (0.04 mL, 0.43 mmol). The reaction was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (2 x 30 mL). The combined organic layers were concentrated to give 2-(3-((benzyloxy)methyl)isoxazol-5-yl)acetic acid (100 mg, 0.40 mmol, 92.5% yield) as a colorless oil. 1 H-NMR (CD3OD-d4, 400MHz): δ12.858(s,1H),7.284-7.387(m,5H),6.334-6.445(s,1H),4.483-4.647(m,4H),3.884-4.031(m,2H).

[0940] Step 6: Ethyl 2-(3-((benzyloxy)methyl)isoxazol-5-yl)acetate

[0941]

[0942] To a solution of 2-(3-((benzyloxy)methyl)isoxazol-5-yl)acetic acid (80.0 mg, 0.32 mmol) in ethanol (5 mL) was added sulfuric acid (0.1 mL, 0.32 mmol). The reaction was stirred at 70 ° C for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (2×30 mL). The combined organic layers were concentrated to give ethyl 2-(3-((benzyloxy)methyl)isoxazol-5-yl)acetate (60 mg, 0.21 mmol, 66.0% yield) as a colorless oil. 15 H 18 NO4[M+H] + LCMS calculated value: 276.1; found: 276.1.

[0943] Step 7: Ethyl 2-(3-((Benzyloxy)methyl)isoxazol-5-yl)-3-methylbutanoate

[0944]

[0945] To a solution of ethyl 2-[3-(phenylmethoxymethyl)-1,2-oxazol-5-yl]acetate (1.0 g, 3.63 mmol) and potassium tert-butoxide (815 mg, 7.26 mmol) in THF (15 mL) was added 2-iodopropane (926 mg, 5.45 mmol) at 0 ° C. The resulting solution was stirred at room temperature for 3 h. The mixture was diluted with EA (20 mL) and washed with water (2 × 10 mL) and brine (1 × 10 mL). The organic layer was separated, dried over MgSO4, and concentrated to dryness to give ethyl 2-(3-((benzyloxy)methyl)isoxazol-5-yl)-3-methylbutanoate (800 mg, 2.52 mmol, 69.4% yield) as an oil.

[0946] Step 8: Ethyl 2-(3-(hydroxymethyl)isoxazol-5-yl)-3-methylbutanoate

[0947]

[0948] To a solution of ethyl 2-(3-((benzyloxy)methyl)isoxazol-5-yl)-3-methylbutanoate (100 mg, 0.32 mmol) in DCM (5 mL) was added phosphorus tribromide (0.05 mL, 0.52 mmol) at -78 ° C. The reaction was stirred at room temperature for 2 h. The mixture was diluted with EA (30 mL) and washed with water (2 × 10 mL) and saturated brine (1 × 10 mL). The organic layer was separated, dried over MgSO4, and concentrated to dryness. The residue was purified by silica gel chromatography (PE: EA = 5: 1) to give ethyl 2-(3-(hydroxymethyl)isoxazol-5-yl)-3-methylbutanoate (50 mg, 0.22 mmol, 69.8% yield) as a colorless oil. 1H-NMR(CD3OD-d4,400MHz): δ6.397(s,1H),4.446-4.516(m,2H),4.097-4.414(m,2H),3.662-3.7 84(m,1H),2.286-2.373(m,1H),1.166-1.286(m,3H),0.892-0.964(m,3H),0.779-0.843(m,3H).

[0949] Step 9: 2-(3-(Hydroxymethyl)isoxazol-5-yl)-3-methylbutanoic acid

[0950]

[0951] To a solution of ethyl 2-(3-(hydroxymethyl)isoxazol-5-yl)-3-methylbutanoate (370 mg, 1.63 mmol) in ethanol (5 mL) was added NaOH (651 mg, 16.3 mmol) at 25 ° C. The resulting solution was stirred at room temperature for 2 h. The mixture was diluted with EA (50 mL) and washed with water (2 × 20 mL) and saturated brine (1 × 10 mL). The organic layer was separated, dried over MgSO4, and concentrated to dryness. The residue was purified by silica gel chromatography (PE: EA = 5: 1) to give 2-(3-(hydroxymethyl)isoxazol-5-yl)-3-methylbutanoic acid (320 mg, 1.6 mmol, 98.7% yield) as a colorless oil. 1 H-NMR(DMSO-d6,400MHz): δ12.90(s,1H),6.364(s,1H),5.453(m,1H),4.469- 4.582(m,2H),3.624-3.645(m,1H),0.954-0.971(m,3H),0.821-0.837(m,3H).

[0952] Step 10: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-(hydroxymethyl)isothiazolinone) (4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0953]

[0954] To a solution of 2-(3-(hydroxymethyl)isoxazol-5-yl)-3-methylbutanoic acid (300.0 mg, 1.51 mmol) in DMF (2 mL) was added (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (1.01 g, 2.26 mmol), HATU (859 mg, 2.26 mmol), and DIEA (0.75 mL, 4.52 mmol). The mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with H O and extracted with EA (20 mL×3). The organic layers were combined and the volatiles were removed under reduced pressure. The residue was purified by silica gel chromatography to give (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-(hydroxymethyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (550 mg, 0.88 mmol, 58.3% yield) as a yellow oil. 32 H 47 N4O5SSi[M+H] + LCMS calculated value: 627.3; found: 627.4.

[0955] Step 11: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-formylisoxazole-5-yl)- 1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0956] To a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-(hydroxymethyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (60 mg, 0.10 mmol) in DCM (2 mL) was added MnO (167 mg, 1.91 mmol). The mixture was stirred at 45 ° C for 1 h. The reaction mixture was diluted with H O and extracted with EA (10 mL×3). The organic layers were combined and the volatiles were removed under reduced pressure. The residue was purified by silica gel chromatography to give (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-formylisoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (40 mg, 0.06 mmol, 66.9% yield) as a yellow oil. 32 H 45 N4O5SSi[M+H] + LCMS calculated value: 625.3; found: 625.2.

[0957] Intermediate 33: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(3-methyl-2-(3-(3-oxygen) ((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxylic acid) Amide

[0958]

[0959] Step 1-10: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-(3-hydroxypropyl) (isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxylic acid Amide

[0960]

[0961] The title compound was prepared using procedures analogous to those described for Int-32 Step 1 to Step 10 with appropriate starting materials. 34 H 51 N4O5SSi[M+H] + LCMS m / z calculated: 655.3; found: 655.3.

[0962] Step 11: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(3-methyl-2-(3-(3-oxo)- (propyl)isoxazol-5-yl)butyryl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide amine

[0963] To a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-(3-hydroxypropyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (80 mg, 0.12 mmol) in MeCN (5 mL) was added IBX (104 mg, 0.24 mmol). The mixture was stirred at 80° C. for 2 h. The reaction was filtered and concentrated in vacuo to afford (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(3-methyl-2-(3-(3-oxopropyl)isoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (80 mg, 0.12 mmol, 100% yield) as a yellow oil. 34 H 49 N4O5SSi[M+H] + LCMS m / z calculated: 653.3; found: 653.3.

[0964] Intermediate 34: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(3-methyl-2-(3-(2-oxygen) ((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxylic acid) Amide

[0965]

[0966] The title compound was prepared using procedures similar to those described for Int-33 with appropriate starting materials. 33 H47 N4O5SSi[M+H] + LCMS m / z calculated: 639.3; found: 639.3.

[0967] Intermediate 35: (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-(((S)-2-(2-hydroxyphenyl)-5,6, 6a,7,9,10-Hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy (2-(2-Methyl-1-Butyryl)-3-(2-Methyl-1-Butyryl)-2-Pyrrolidine-2-Carboxylic Acid)

[0968]

[0969] Step 1: (2S,4R)-1-((R)-2-(3-(2-bromoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4- Methyl ((tert-Butyldimethylsilyl)oxy)pyrrolidine-2-carboxylate

[0970]

[0971] To a solution of 1,2-dibromoethane (15.3 g, 81.6 mmol) and methyl (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((R)-2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl)pyrrolidine-2-carboxylate (3.5 g, 8.16 mmol) in DMF (5 mL) was added potassium carbonate (3.4 g, 24.5 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EA (50 mL) and washed with water (2×20 mL) and saturated brine (1×10 mL). The organic layer was separated, dried over MgSO 4 , and concentrated to dryness. The residue was purified by preparative HPLC, eluting with 5.0% to 95% CH3CN in H2O (0.1% NH3.H2O) to give (2S,4R)-methyl 1-((R)-2-(3-(2-bromoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylate (1.0 g, 1.87 mmol, 22.9% yield). 22 H 38 BrN2O6Si[M+H] + LCMS m / z calculated: 533.2; found: 533.3.

[0972] Step 2: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((R)-2-(3-(2-(4-(((S)- 2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl) (methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid methyl ester

[0973]

[0974] To a solution of (S)-2-(8-(piperidin-4-ylmethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (60 mg, 0.16 mmol) and (2S,4R)-1-((R)-2-(3-(2-bromoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylic acid methyl ester (92.5 mg, 0.17 mmol) in DMF (5 mL) was added NaHCO (132 mg, 1.58 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with EA (50 mL) and washed with water (2×20 mL) and brine (1×10 mL). The organic layer was dried over MgSO4 and concentrated to dryness. The residue was purified by silica gel chromatography to give (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((R)-2-(3-(2-(4-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid methyl ester (18.0 mg, 0.021 mmol, 13.7% yield). 43 H 65 N8O7Si[M+H] + LCMS m / z calculated: 833.5; found: 833.3.

[0975] Step 3: (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7, 9,10-Hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)iso (3-(2-(2-oxazol-5-yl)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid)

[0976]

[0977] To a solution of methyl (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((R)-2-(3-(2-(4-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)pyrrolidine-2-carboxylate (30.0 mg, 0.04 mmol) in THF (2 mL) and water (2 mL) was added LiOH (15.1 mg, 0.36 mmol) at room temperature. The reaction was stirred at room temperature for 16 h. The mixture was diluted with EA (30 mL) and washed with water (2 x 10 mL) and brine (1 x 10 mL). The organic layer was dried over MgSO4 and concentrated to dryness. The residue was purified by preparative HPLC eluting with MeCN in H2O (0.1% HCl) to afford the de-TBS product (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid (18.0 mg, 0.025 mmol, 70.9% yield). 36 H 49 N8O7[M+H] + LCMS m / z calculated: 705.4; found: 705.5.

[0978] Intermediate 36: 2-(6-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3- c]pyridazin-2-yl)phenol

[0979]

[0980] Step 1: tert-Butyl 4-(3,6-dichloropyridazin-4-yl)-3-formylpiperazine-1-carboxylate

[0981]

[0982] To a solution of tert-butyl 4-(3,6-dichloropyridazin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (3.96 g, 10.9 mmol) in DCM (70 mL) was added Dess-Martin periodinane (9.25 g, 21.8 mmol) at 0 ° C. The mixture was stirred at 0 ° C for 1 h. The reaction was quenched with saturated aqueous Na2S2O3 (80 mL) and extracted with DCM (80.0 mL×3). The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure to give crude tert-butyl 4-(3,6-dichloropyridazin-4-yl)-3-formylpiperazine-1-carboxylate (3.6 g, 9.97 mmol, 91.4% yield). 14 H 19 Cl2N4O3[M+H] + LCMS m / z calculated: 361.1; found: 361.1.

[0983] Step 2: tert-Butyl 4-(3,6-dichloropyridazin-4-yl)-3-(1-hydroxyethyl)piperazine-1-carboxylate

[0984]

[0985] To a solution of tert-butyl 4-(3,6-dichloropyridazin-4-yl)-3-formylpiperazine-1-carboxylate (3.6 g, 9.97 mmol) in THF (70 mL) was added CH3MgBr (1 M in Et2O, 19.9 mL, 19.9 mmol) at 0°C. The mixture was stirred at 0°C for 2 h. The reaction was quenched with saturated aqueous NH4Cl solution (80 mL) and extracted with EA (80 mL×3). The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EA=3:1) to give tert-butyl 4-(3,6-dichloropyridazin-4-yl)-3-(1-hydroxyethyl)piperazine-1-carboxylate (2.1 g, 5.6 mmol, 56.9% yield) as a yellow solid. C 15 H 23 Cl2N4O3[M+H] + LCMS m / z calculated: 377.1; found: 377.0.

[0986] Step 3 to Step 7: 2-(6-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino [2,3-c]pyridazin-2-yl)phenol

[0987] The title compound was prepared using procedures similar to those described for Int-9 step 2 to step 6 with appropriate starting materials. 16 H 20 N5O[M+H] + LCMS m / z calculated: 298.2; found: 298.2. 1H NMR (400MHz, CD3OD): δ7.75-7.78(m,1H),7.16-7.24(m,2H),6.87-6.90(m,2H),3.91-4.07(m,1H),3.35-3 .48(m,1H),3.11-3.30(m,2H),2.99-3.09(m,1H),2.83-2.92(m,2H),2.46-2.65(m,1H),1.22-1.29(m,3H).

[0988] Intermediate 37. (2S,4R)-1-((2R)-2-(3-((1-bromopropyl-2-yl)oxy)isoxazol-5-yl)-3-methyl butyryl)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl 1-Methyl-2-pyrrolidine-2-carboxamide

[0989]

[0990] To a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((R)-2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (300 mg, 0.49 mmol), 1-bromopropan-2-ol (292 mg, 1.47 mmol) and triphenylphosphine (385 mg, 1.47 mmol) in THF (10 mL) was added diisopropyl azodicarboxylate (297 mg, 1.47 mmol) dropwise at 0° C. The resulting solution was stirred at room temperature for 16 h. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography (PE:EA=2:1) ​​to give (2S,4R)-1-((2R)-2-(3-((1-bromopropan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (300 mg, 0.41 mmol, 83.5% yield). 34 H 50 BrN4O5SSi[M+H] + LCMS m / z calculated: 733.2; found: 733.4.

[0991] Intermediate 38. (S)-2-(8-(2-aminoethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4, 5]pyrazino[2,3-c]pyridazin-2-yl)phenol

[0992]

[0993] Step 1: (S)-(2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5] tert-Butyl pyrazino[2,3-c]pyridazin-8-yl)ethyl)carbamate

[0994]

[0995] A mixture of (R)-2-(6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (29 mg, 0.10 mmol), tert-butyl (2-bromoethyl)carbamate (24.1 mg, 0.11 mmol) and NaHCO (82.1 mg, 0.98 mmol) in DMF (3 mL) was stirred at 65 ° C for 16 h. The reaction mixture was diluted with EA (40 mL) and washed with H O (15 mL × 3) and brine (30 mL). The organic layer was separated, dried over Na SO, filtered, and then concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH=10:1) to give tert-butyl (S)-(2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)ethyl)carbamate (40 mg, 0.094 mmol, 95.9% yield) as a light yellow solid. 22 H 31 N6O3[M+H] + LCMS m / z calculated: 427.2; found: 427.1.

[0996] Step 2: (S)-2-(8-(2-aminoethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5] ... (2,3-c)pyridazin-2-yl)phenol

[0997] To a solution of tert-butyl (S)-(2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)ethyl)carbamate (40 mg, 0.094 mmol) in DCM (10 mL) was added TFA (1.0 mL). The mixture was stirred at 25 °C for 10 h. The volatiles were removed under reduced pressure to give crude (S)-2-(8-(2-aminoethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol as its TFA salt (40 mg). 17 H 23 N6O[M+H] + LCMS m / z calculated: 327.2; found: 327.2.

[0998] Intermediate 39. (S)-1-(2-Fluoro-4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine

[0999]

[1000] Step 1: tert-Butyl (S)-(1-(4-bromo-2-fluorophenyl)ethyl)carbamate

[1001]

[1002] TEA (2.1 mL, 15.0 mmol) was added to a solution of (S)-1-(4-bromo-2-fluorophenyl)ethan-1-amine (1.0 g, 5 mmol) and di-tert-butyl dicarbonate (1.6 g, 7.5 mmol) in DCM (10 mL). The resulting solution was stirred at 25 ° C for 1.5 h. The reaction mixture was washed with water (3×10 mL). The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl (S)-(1-(4-bromo-2-fluorophenyl)ethyl)carbamate (1.2 g, 3.8 mmol, 76.0% yield) as a colorless solid. 13 H 18 BrFNO2[M+H] + LCMS m / z calcd: 318.0; found: 318.0.

[1003] Step 2: (S)-tert-Butyl(1-(2-fluoro-4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate

[1004]

[1005] Palladium acetate (5.71 mg, 0.03 mmol) was added to a solution of tert-butyl (S)-(1-(4-bromo-2-fluorophenyl)ethyl)carbamate (90.0 mg, 0.25 mmol), potassium acetate (50 mg, 0.51 mmol) and 4-methyl-1,3-thiazole (50.5 mg, 0.51 mmol) in DMF (2 mL). The resulting solution was purged with nitrogen three times. The reaction mixture was heated to 90 ° C and stirred for 16 h. The combined reaction mixture was diluted with EtOAc (25 mL) and washed with water (4×10 mL). The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC with PE / EA (6 / 1) to give tert-butyl (S)-(1-(2-fluoro-4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate (36 mg, 0.093 mmol, 36.5% yield). 17 H 22 FN2O2S[M+H] + LCMS m / z calculated: 337.1; found: 337.3.

[1006] Step 3: (S)-1-(2-Fluoro-4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine

[1007] TFA (1.0 mL) was added to a solution of (S)-tert-butyl(1-(2-fluoro-4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate (15 mg, 0.04 mmol) in DCM (5 mL). The resulting solution was stirred at 25 °C for 3 h. The volatiles were removed under reduced pressure to afford (S)-1-(2-fluoro-4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine (10 mg, 0.04 mmol, 94.9% yield) as an oil. 12 H 14 FN2S[M+H] + LCMS m / z calculated: 237.1; found: 237.1.

[1008] Intermediate 40. (S)-1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)ethan-1-amine

[1009]

[1010] Step 1: tert-Butyl (S)-(1-(4-bromophenyl)ethyl)carbamate

[1011]

[1012] The title compound was prepared using procedures analogous to those described for Int-39 Step 1 with appropriate starting materials. 11 BrNO2[M+H-tBu] + LCMS m / z calculated: 244.0; found: 244.2.

[1013] Step 2: (S)-tert-Butyl(1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)ethyl)carbamate

[1014]

[1015] CuI (74 mg, 0.39 mmol) was added to a solution of (S)-tert-butyl (1-(4-bromophenyl)ethyl)carbamate (1.2 g, 3.9 mmol), 2-methyl-1H-imidazole (640 mg, 7.8 mmol), cesium carbonate (2.5 g, 7.8 mmol) and proline (899 mg, 7.8 mmol) in DMSO (3 mL). The resulting solution was purged with nitrogen three times. The reaction mixture was heated to 130 ° C and stirred for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EA (3×20 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by preparative TLC with EA / PE (2 / 1) to give tert-butyl (S)-(1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)ethyl)carbamate (120 mg, 0.38 mmol, 9.7% yield) as a yellow oil. 17 H 24N3O2[M+H] + LCMS m / z calculated: 302.2; found: 302.1

[1016] Step 3: (S)-1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)ethan-1-amine

[1017] TFA (1.0 mL) was added to a solution of (S)-tert-butyl(1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)ethyl)carbamate (15 mg, 0.05 mmol) in DCM (5 mL). The resulting solution was stirred at 25 °C for 3 h. The volatiles were removed under reduced pressure to afford (S)-1-(2-fluoro-4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine (10 mg, 0.05 mmol, 99.8% yield) as an oil. 12 H 16 N3[M+H] + LCMS m / z calculated: 202.1; found: 202.1.

[1018] Intermediate 41. (S)-1-(2-methoxy-4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine

[1019]

[1020] Step 1: (S,E)-N-(1-(4-bromo-2-methoxyphenyl)ethylidene)-2-methylpropane-2-sulfenamide

[1021]

[1022] To a solution of 1-(4-bromo-2-methoxyphenyl)ethanone (1.0 g, 4.4 mmol) in THF (10 mL) was added titanium ethoxide (2.0 g, 8.7 mmol) and (R)-tert-butanesulfenamide (635 mg, 5.24 mmol). After purging with N2 three times, the mixture was stirred at 70 ° C for 12 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (3×30 mL). The organic layers were combined, washed with brine, concentrated in vacuo, and the residue was purified by silica gel chromatography (PE: EA = 20: 1 to 3: 1) to give (S, E) -N- (1- (4-bromo-2-methoxyphenyl) ethylidene) -2-methylpropane-2-sulfenamide (400 mg, 1.2 mmol, 27% yield) as a yellow oil. 13 H 19 BrNO2S[M+H] + LCMS m / z calcd: 332.0; found: 332.0.

[1023] Step 2: N-((S)-1-(4-bromo-2-methoxyphenyl)ethyl)-2-methylpropane-2-sulfenamide

[1024]

[1025] To a solution of (S,E)-N-(1-(4-bromo-2-methoxyphenyl)ethylidene)-2-methylpropane-2-sulfinamide (400 mg, 1.2 mmol) in THF (20 mL) was added lithium tri-sec-butylborohydride (1 M, 8.73 mL, 8.73 mmol) at 0 ° C. After purging with N2 three times, the mixture was stirred at 70 ° C for 12 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (3×30 mL). The organic layers were combined, washed with brine, concentrated in vacuo, and the residue was purified by silica gel chromatography (PE:EA=20:1 to 1:1) to give N-((S)-1-(4-bromo-2-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (206 mg, 0.59 mmol, 51.2% yield) as a yellow oil. 13 H 21 BrNO2S[M+H] + LCMS m / z calculated: 334.0; found: 334.1.

[1026] Step 3: N-((S)-1-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) (phenyl)ethyl)-2-methylpropane-2-sulfenamide

[1027]

[1028] To a solution of N-((S)-1-(4-bromo-2-methoxyphenyl)ethyl)-2-methylpropane-2-sulfenamide (175 mg, 0.52 mmol) and bis(pinacolato)diboron (200 mg, 0.79 mmol) in 1,4-dioxane (5 mL) was added Pd(dppf)Cl2 (38 mg, 0.05 mmol) and potassium acetate (154 mg, 1.57 mmol). The resulting solution was stirred at 90 ° C. under N2 atmosphere for 16 h. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography (PE:EA = 10:1 to 1:1) to give N-((S)-1-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfenamide (160 mg, 0.4 mmol, 76.8% yield) as a solid. 19 H 33 BNO4S[M+H] + LCMS m / z calculated: 382.2; found: 382.3.

[1029] Step 4: N-((S)-1-(2-methoxy-4-(4-methylthiazol-5-yl)phenyl)ethyl)-2-methylpropane-2-yl Sulfenamide

[1030]

[1031] To a solution of N-((S)-1-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfenamide (100 mg, 0.26 mmol) and 5-bromo-4-methyl-1,3-thiazole (70 mg, 0.39 mmol) in 1,4-dioxane (5 mL) was added Pd(dppf)Cl2 (19 mg, 0.03 mmol) and potassium acetate (77 mg, 0.79 mmol). The resulting solution was stirred at 90 ° C. under N2 atmosphere for 16 h. The volatiles were removed under reduced pressure and the residue was purified by preparative TLC (DCM:MeOH=20:1) to give N-((S)-1-(2-methoxy-4-(4-methylthiazol-5-yl)phenyl)ethyl)-2-methylpropane-2-sulfenamide (50 mg, 0.14 mmol, 52% yield) as a solid. 17 H 25 N2O2S2[M+H] + LCMS m / z calculated: 353.1; found: 353.3.

[1032] Step 5: (S)-1-(2-methoxy-4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine

[1033] A solution of N-((S)-1-(2-methoxy-4-(4-methylthiazol-5-yl)phenyl)ethyl)-2-methylpropane-2-sulfenamide (100 mg, 0.28 mmol) in HCl in dioxane (1 M, 1.42 mL, 1.42 mmol) was stirred at room temperature for 2 h. The volatiles were removed under reduced pressure to afford (S)-1-(2-methoxy-4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine (60 mg, 0.24 mmol, 85% yield) as a yellow solid, which was used directly in the next step. 13 H 17 N2OS[M+H] + LCMS m / z calculated: 249.1; found: 249.2.

[1034] Intermediate 45. (2S,4R)-1-(2-(3-(2-bromoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4- ((tert-Butyldimethylsilyl)oxy)-N-((R)-2-((tert-Butyldimethylsilyl)oxy)-1-(4-(4-methyl) (5-(2-Methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[1035]

[1036] Step 1: tert-Butyl (R)-(1-(4-bromophenyl)-2-((tert-butoxycarbonyl)oxy)ethyl)carbamate

[1037]

[1038] To a solution of (2S)-2-amino-2-(4-bromophenyl)ethanol (1.0 g, 4.6 mmol) in DCM (100 mL) was added di-tert-butyl dicarbonate (3.0 g, 13.9 mmol) and triethylamine (3.2 mL, 23.1 mmol). The mixture was stirred at room temperature for 16 h. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography (PE: EA = 100: 1 to 5: 1) to give (R)-tert-butyl (1-(4-bromophenyl)-2-((tert-butoxycarbonyl)oxy)ethyl)carbamate (1.4 g, 3.4 mmol, 72.6% yield) as a colorless oil. 18 H 27 BrNO5[M+H] + LCMS m / z calculated for: 416.1; found: 416.1.

[1039] Step 2: (R)-(2-((tert-Butoxycarbonyl)oxy)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)amino tert-Butyl formate

[1040]

[1041] The title compound was prepared using procedures analogous to those described for Int-39, Step 2, with appropriate starting materials. 22 H 31 N2O5S[M+H] + LCMS m / z calculated: 435.2; found: 435.1.

[1042] Step 3: (R)-2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-ol

[1043]

[1044] To a solution of tert-butyl (R)-(2-((tert-butoxycarbonyl)oxy)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate (1.0 g, 2.3 mmol) in DCM (10 mL) was added TFA (10 mL). The mixture was stirred at room temperature for 2 h. The volatiles were removed under reduced pressure to afford (R)-2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-ol (741 mg, 2.2 mmol, 99% yield) as a brown oil. 12 H 15 N2OS[M+H] + LCMS m / z calculated: 235.1; found: 235.2.

[1045] Step 4: (R)-2-((tert-Butyldimethylsilyl)oxy)-1-(4-(4-methylthiazol-5-yl)phenyl) Ethan-1-amine

[1046]

[1047] To a solution of (R)-2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-ol (850 mg, 3.63 mmol) in DCM (10 mL) was added imidazole (741 mg, 10.9 mmol) and tert-butyldimethylsilyl chloride (820 mg, 5.44 mmol). The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with DCM. The organic layers were combined, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (DCM:MeOH=20:1) to give (R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine (500 mg, 1.24 mmol, 34.3% yield) as a yellow oil. 18 H 29 N2OSSi[M+H] + LCMS m / z calculated: 349.2; found: 349.2.

[1048] Step 5: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-((R)-2-((tert-butyldimethyl) (2-(3-hydroxyisoxazol-5-yl)-3-methylthiazol-5-yl)phenyl)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)-1-(2-(3-hydroxyisoxazol-5-yl)-3-methylthiazol-5-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)-1-(2-(3-hydroxyisoxazol-5-yl (2-(2-aminobutyryl)pyrrolidine-2-carboxamide)

[1049]

[1050] To a stirred solution of (R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine (360 mg, 1.03 mmol) and (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid (639 mg, 1.55 mmol) in DMF (10 mL) was added HATU (141 mg, 2.07 mmol) and DIPEA (0.54 mL, 3.1 mmol) at room temperature. After 16 h, water (20 ml) was added and the resulting mixture was extracted with EA (20 mL x 3). The organic layers were combined, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by gel chromatography (DCM:MeOH=20:1) to give (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-((R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)-1-(2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl)pyrrolidine-2-carboxamide (200 mg, 0.23 mmol, 22.6% yield) as a yellow solid. 37 H 59 N4O6SSi2[M+H] +LCMS m / z calculated: 743.4; found: 743.5.

[1051] Step 6: (2S,4R)-1-(2-(3-(2-bromoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-((tert-butyl (tert-butyldimethylsilyl)oxy)-N-((R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(4-methylthiazole) (5-oxazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[1052] To a stirred solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-((R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)-1-(2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl)pyrrolidine-2-carboxamide (40.0 mg, 0.05 mmol) and 1,2-dibromoethane (15.2 mg, 0.08 mmol) in DMF (10 mL) was added potassium carbonate (0.06 mL, 0.11 mmol) at room temperature. After 16 h, water (20 ml) was added and the resulting mixture was extracted with EA (20 mL x 3). The organic layers were combined, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (DCM:MeOH=20:1) to give (2S,4R)-1-(2-(3-(2-bromoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-((R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (40.6 mg, 0.048 mmol, 89.2% yield) as a yellow solid. 39 H 62 BrN4O6SSi2[M+H] + LCMS m / z calculated: 849.3; found: 849.5.

[1053] Intermediate 50. (2S,4R)-1-(2-(3-((1-bromobutan-2-yl)oxy)isoxazol-5-yl)-3-methylbutyryl 1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidone Pyrrolidine-2-carboxamide

[1054]

[1055] The title compound was prepared using procedures similar to those described for Int-37 with appropriate starting materials. 35 H 52 BrN4O5SSi[M+H] + LCMS m / z calculated: 747.3; found: 747.3.

[1056] Intermediate 52. (2S,4R)-1-((S)-2-(2-(2-chloroethoxy)acetamido)-3,3-dimethylbutanoyl)- 4-Hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[1057]

[1058] To a solution of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (50 mg, 0.11 mmol) in DMF (2 mL) was added (2-chloroethoxy)acetic acid (18.7 mg, 0.13 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (64 mg, 0.17 mmol) and TEA (0.08 mL, 0.45 mmol). The mixture was stirred at 110 ° C. under N2 atmosphere for 4 h. The reaction was quenched with H2O and extracted with EA (10.0 mL×3). The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (DCM:MeOH=10:1) to give (2S,4R)-1-((S)-2-(2-(2-chloroethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (57 mg, 0.10 mmol, 89.7% yield) as a white solid. 27 H 38 ClN4O5S[M+H] + LCMS m / z calculated: 565.2; found: 565.0.

[1059] Intermediate 59. 3-(2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5] ... (2,3-c)pyridazin-8-yl)propanal

[1060]

[1061] Step 1: 2-(8-(2-(1,3-dioxolan-2-yl)ethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino [1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol

[1062]

[1063] To a stirred solution of 2-(6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (60 mg, 0.21 mmol) in DMF (2 mL) was added 2-(2-bromoethyl)-1,3-dioxolane (96 mg, 0.53 mmol) and potassium carbonate (218 mg, 1.58 mmol) at room temperature. After 2 h, the volatiles were removed and the residue was then purified by preparative TLC (EA) to give the desired product (40 mg, 0.10 mmol, 48% yield) as a white solid. 20 H 26 N5O3[M+H] +LCMS m / z calculated: 384.4; found: 384.2.

[1064] Step 2: 3-(2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino [2,3-c]pyridazin-8-yl)propanal

[1065] To a stirred solution of 2-(8-(2-(1,3-dioxolane-2-yl)ethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (60 mg, 0.16 mmol) in MeCN (2 mL) was added aqueous HCl (1 N, 1 mL) at room temperature. After 16 h, the reaction mixture was quenched with aqueous NaHCO3 and extracted with EA (30 mL). The organic layer was concentrated to give 3-[4-(2-hydroxyphenyl)-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradec-2,4,6-trien-12-yl]propanal (35 mg, 0.10 mmol, 65.9% yield). 18 H 22 N5O2[M+H] + LCMS m / z calculated: 340.2; found: 340.1.

[1066] Intermediate 60. (2S,4R)-4-hydroxy-1-((2R)-3-methyl-2-(3-(pyrrolidin-3-yloxy)isoxazole- 5-yl)butyryl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[1067]

[1068] Step 1: 3-((5-((R)-1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1- (4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)iso tert-Butyl oxazol-3-yl)oxy)pyrrolidine-1-carboxylate

[1069]

[1070] A mixture of (2S,4R)-4-((tert-butyldimethyls...

Claims

1. A compound of formula IA-13a, IA-13b, IA-14a or IA-14b below: Wherein X is N or CH, Each R k Independently C 1-3 Alkyl, and s=0 or 1; R 1 for: -(CR 1a R 1b ) 1-5 -, -(CR 1a R 1b ) 1-5 -O-, -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -, where A is O or NR 1c , -(CR 1a R 1b ) 1-5 -(3-11 membered heterocyclic group)-, -(CR 1a R 1b ) 1-5 -(3-11 membered heterocyclyl)-O-, -(CR 1a R 1b ) 1-5 -(3-11 membered heterocyclyl)-(CR 1a R 1b ) 1-5 -, -(CR 1a R 1b ) 1-5 -(3-11 membered heterocyclyl)-(CR 1a R 1b ) 1-5 -O-, -(3-11 membered heterocyclyl)-(CR 1a R 1b ) 1-5- , -(3-11 membered heterocyclyl)-(CR 1a R 1b ) 1-5 -O-, -(3-11-membered heterocyclyl)-(3-11-membered heterocyclyl)-(CR 1a R 1b ) 1-5 -O-, -(3-11 membered heterocyclyl)-(CR 1a R 1b ) 1-5 -(3-11 membered heterocyclyl)-(CR 1a R 1b ) 1-5 -O-, -(3-11-membered heterocyclyl)-(CO)-(CR 1a R 1b ) 1-5 -O-, -(3-11-membered heterocyclyl)-(CO)-O-(CR 1a R 1b ) 1-5 -, -(CO)-(3-11-membered heterocyclyl)-(CR 1a R 1b ) 1-5 -O-, or -A-(3-11 membered heterocyclyl)-(CR 1a R 1b ) 1-5 -A-, wherein A is independently O or NR 1c , where R 1a H, R 1b is H or C1-C4 alkyl, and R 1c is H or C1-C4 alkyl, and the heterocyclic group contains 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur.

2. The compound according to claim 1, wherein R 1 -(3-11 membered heterocyclic)-(CR 1a R 1b ) 1-3 -O-, where each R 1a For H and each R 1b are independently H or -C1-C4 alkyl.

3. The compound according to claim 1, wherein R 1 -(3-11 membered heterocyclic)-(CO)-(CR 1a R 1b ) 1-3 -O-, where each R 1a For H and each R 1b are independently H or -C1-C4 alkyl.

4. The compound of claim 1, wherein the compound is a compound of Formula IA-15a, IA-15b, IA-16a, or IA-16b: Where A is O, R 1a1 is H or -C1-C4 alkyl; R 1c is -H or -C1-C4 alkyl; A 1 For covalent bonds or -(CR 1a R 1b ) 1-3 .

5. The compound according to claim 4, wherein A is O and R 1a1 It is a -C1-C4 alkyl group.

6. The compound according to claim 4, wherein A 1 It is a covalent bond.

7. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is: (2S,4R)-4-hydroxy-1-((S)-2-(2-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((S)-2-(2-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((S)-2-(2-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)acetamido)-3,3-dimethylbutanoyl)-N-(4-(5-methylthiazol-4-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((S)-2-(2-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)acetamido)-3,3-dimethylbutanoyl)-N-(4-(5-methylthiazol-4-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-4-methylpiperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((S)-2-(3-(2-(4-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((S)-2-(3-(2-(4-(((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((S)-2-(4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)butanamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((S)-2-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)butanamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; 2-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)ethyl((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate; 2-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)ethyl((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate; (2S,4R)-4-hydroxy-1-((S)-2-(3-(4-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propionamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((S)-2-(3-(4-(((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propionamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (3R,5S)-1-((R)-2-(3-(2-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl acetate; (3R,5S)-1-((R)-2-(3-(2-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-acetate; (3R,5S)-1-((R)-2-(3-(2-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl isobutyrate; (3R,5S)-1-((R)-2-(3-(2-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl isobutyrate; (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(6-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-monoheterobicyclo[3.1.1]hept-3-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(6-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-monoheterobicyclo[3.1.1]hept-3-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(6-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)-2-azaspiro[3.3]hept-2-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(6-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)-2-azaspiro[3.3]hept-2-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(((R)-1-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(((S)-1-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(((R)-1-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(((S)-1-(4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((S)-3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((R)-3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((S)-3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((R)-3-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(((S)-1-((S)-3-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(((S)-1-((S)-3-(((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(((S)-1-((R)-3-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(((S)-1-((R)-3-(((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(((R)-1-((S)-3-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(((R)-1-((S)-3-(((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(((R)-1-((R)-3-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(((R)-1-((R)-3-(((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((S)-3-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((R)-3-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((R)-3-(4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((S)-3-(4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((S)-3-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((S)-3-(4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((R)-3-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((R)-3-(4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3S,4R)-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)-2-oxoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3S,4S)-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)-2-oxoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3R,4R)-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)-2-oxoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3R,4S)-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)-2-oxoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3S,4R)-4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)-2-oxoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3R,4R)-4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)-2-oxoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3R,4S)-4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)-2-oxoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3S,4S)-4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)-2-oxoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((S)-3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((R)-3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((R)-3-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((S)-3-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(((S)-1-((R)-3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(((S)-1-((S)-3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(((S)-1-((S)-3-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(((S)-1-((R)-3-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(((R)-1-((R)-3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(((R)-1-((S)-3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(((R)-1-((S)-3-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(((R)-1-((R)-3-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((2R,4R)-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-2-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((2S,4R)-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-2-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((2R,4S)-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-2-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((2S,4S)-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-2-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((2R,4R)-4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-2-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((2S,4R)-4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-2-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((2R,4S)-4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-2-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((2S,4S)-4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-2-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3R,4S)-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3S,4R)-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3R,4R)-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3S,4S)-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3R,4S)-4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3S,4R)-4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3R,4R)-4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((3S,4S)-4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-((S)-1-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)ethyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-((R)-1-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)ethyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-((S)-1-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)ethyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-((R)-1-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)ethyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-((R)-3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-((S)-3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-((S)-3-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-((R)-3-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((S)-3-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((R)-3-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((R)-3-(((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((S)-3-(((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(3-((S)-3-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(3-((R)-3-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(3-((R)-3-(((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(3-((S)-3-(((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2S)-2-(2-(2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-Hydroxy-N-[[4-(5-methyl-1,3-thiazol-4-yl)phenyl]methyl]-1-[(2S)-2-[[2-[4-(2-hydroxyphenyl)-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradec-2,4,6-trien-12-yl]acetyl]amino]-3,3-dimethylbutanoyl]pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2S)-2-(2-(4-((2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-Hydroxy-1-((2R)-2-(3-(2-(2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methyl-1λ 3 ,3λ 2 -thiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2S)-2-(3-(2-(4-((2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2S)-2-(4-(2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)butanamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; 2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)ethyl((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate; (2S,4R)-4-hydroxy-1-((2S)-2-(3-(4-((2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propionamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2S)-2-(2-(2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)ethoxy)acetylamino)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2S)-2-(2-(3-(2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)azetidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; 2-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethyl ((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (3R,5S)-1-((2R)-2-(3-(2-(2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl acetate; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(6-(2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-azabicyclo[3.1.1]hept-3-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(6-(2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)-2-azaspiro[3.3]hept-2-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((2R)-2-(3-(2-(3-fluoro-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(3-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)azepan-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-((1-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-((4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-(2-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethyl)piperazin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-(2-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-((1-(3-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(3-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-((4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)cyclohexyl)(methyl)amino)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-[1,4'-bipiperidinyl]-1'-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)-1-(2-(3-(2-(4-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(5-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (3R,5S)-1-((R)-2-(3-(2-(4-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl isobutyrate; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-2-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(4-(1-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)ethyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-(2-(3-((1-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)butan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-(2-(3-((1-(3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)butan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-((1-(4-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)azepan-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(4-(3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-((R)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(3-((2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (3R,5S)-1-((R)-2-(3-(2-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl isobutyrate; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(4-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)azepan-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(3-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(4-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-3,3-dimethylpiperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-3,6-dihydropyridin-1(2H)-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(3-hydroxy-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(3-hydroxy-4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(4-(2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(((2S)-1-(4-(2-(2-hydroxyphenyl)-6-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-((S)-2-(2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(4-((2-(2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)(methyl)amino)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(((S)-1-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)-1-oxopropan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-(2-(3-(((2R)-1-(3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)-1-oxopropan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)-3-methylpiperidin-1-yl)-2-oxoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(((R)-1-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)-1-oxopropan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-(2-(3-((4-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)methyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(3-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)propyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-((4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)methyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)propyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(3-(2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)propyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(3-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidin-1-yl)ethyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-(2-(3-(2-((2-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)ethyl)(methyl)amino)ethyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(3-((2-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)ethyl)(methyl)amino)propyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-N-((S)-1-(4-cyanophenyl)ethyl)-4-hydroxy-1-((R)-2-(3-(2-(4-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)pyrrolidine-2-carboxamide; (2S,4R)-N-((S)-1-(2-fluoro-4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxy-1-((R)-2-(3-(2-(4-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(2-methoxy-4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(((2S)-1-(3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(((2R)-1-(3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(((S)-1-(4-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)propan-2-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((R)-2-(3-(2-(4-(((6aS,9S)-2-(2-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2R)-2-(3-(2-(3-((6aS,9S)-2-(2-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (5-(1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)methyl 4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidine-1-carboxylate; (2S,4R)-4-hydroxy-1-(2-(3-(((4-(2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]pyridazin-8-yl)pyridin-2-yl)oxy)methyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((2S)-2-(1-(3-(2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)propyl)azetidine-3-carboxamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; or (2S,4R)-4-Hydroxy-1-((2R)-2-(3-((1-(3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)propyl)pyrrolidin-3-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

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

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

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

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 and a pharmaceutically acceptable excipient.

12. Use of a compound according to any one of claims 1 to 10 in the preparation of a medicament for treating cancer in a subject in need thereof.

13. The use according to claim 12, wherein the cancer contains a SMARCA4 mutation.

14. The method of claim 12, wherein the cancer is selected from the group consisting of squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer; leukemia; benign and malignant lymphomas; benign and malignant melanomas; myeloproliferative diseases; sarcomas, gliomas, astrocytomas, oligodendrogliomas, ependymomas, glioblastomas, neuroblastomas, gangliocytomas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningiosarcomas, neurofibromas and schwannomas; uterine cancer, testicular cancer, thyroid cancer, carcinosarcoma, Hodgkin's disease, Wilms' tumor or teratoma.

15. The use according to claim 14, wherein the leukemia is T-lineage acute lymphoblastic leukemia (T-ALL), adult T-cell leukemia, precursor B ALL, B-cell ALL, Philadelphia chromosome-positive ALL or Philadelphia chromosome-positive CML.

16. The use according to claim 14, wherein the lymphoma is T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, precursor B lymphoma, large B-cell lymphoma or Burkitt's lymphoma.

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