BRM-targeted compounds and related methods of use

Abstract

The present invention provides compounds that inhibit SMARCA2 (BRM) and / or SMARCA4 for the treatment of cancer. [Solution] A bifunctional compound is provided, represented by formula (I), which includes a target protein binding moiety and an E3 ubiquitin ligase binding moiety. JPEG2026143434000318.jpg8128 In equation (I), PTM is part of equation IA, JPEG2026143434000319.jpg33128 ULM is a small molecule that binds to von Hippel-Lindau E3 ubiquitin ligase, specifically the E3 ubiquitin ligase binding portion.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to U.S. Provisional Patent Application No. 63 / 036,811, filed on 9 June 2020, which is incorporated herein by reference in its entirety.

[0002] (Field of invention) This specification provides bifunctional compounds comprising a target protein-binding moiety and an E3 ubiquitin ligase-binding moiety, as well as related methods of use. The bifunctional compounds are particularly useful as modulators of targeted ubiquitination with respect to chromatin, subfamily A, member 2, switch / sucrose non-fermentable (SWI / SNF)-related, matrix-associated, actin-dependent regulator of chromatin (i.e., BRAHMA or BRM), which are degraded and / or inhibited by the bifunctional compounds of this disclosure. [Background technology]

[0003] Human switch / sucrose non-fermentable (SWI / SNF) complexes are ATP-dependent chromatin reconstitutes. These large complexes play crucial roles in essential cellular processes such as transcription, DNA repair, and replication by regulating DNA accessibility.

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

[0005] SMARCA2(BRM) and SMARCA4(BRG1) are subunits containing catalytic ATPase domains, which are essential for the function of SWI / SNF in disrupting histone-DNA contact and thereby providing access points to transcription factors and congeneral DNA elements that facilitate gene activation and repression.

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

[0007] Previous studies have demonstrated potent synthetic lethality using gene expression manipulation such as RNAi, showing that downregulation of SMARCA2 gene expression in SMARCA4-mutated cancer cells leads to suppression of cancer cell proliferation. However, SMARCA2 / 4 bromodomain inhibitors (e.g., PFI-3) show little to no effect on inhibiting cell proliferation [Vangamudi et al. Cancer Res 2015]. This phenotypic discrepancy between downregulation of gene expression and small molecule-based approaches led us to investigate bispecific proteolytic molecules in SMARCA4-deficient cancer.

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

[0009] Therapeutic compounds that inhibit SMARCA2 and / or SMARCA4 are needed. [Overview of the project]

[0010] This disclosure relates to a compound of formula I,

[0011] [ka] Or with respect to the pharmaceutically acceptable salt or solvate thereof, During the ceremony, PTM is part of formula IA,

[0012] [ka] During the ceremony, R 1 This is a covalent bond, or a chemical moiety that links PTM and ULM. * This is the connection point to ULM, n = 0 to 3, W is a -CH2-, -C(O)-, -S(O)-, or -S(O)2- which is substituted by any choice, and if n=2 or 3, then only one W can be -C(O)-, -S(O)-, or -S(O)2-. R c1 and R d1 These are H, D, Halo, and C, independently. 1~3 Alkyl, C 1~3 Haloalkyl, or C 1~4 It is an alkoxyl, R e3is H, -C(O)R f , or -P(O)(OR g )2, wherein R f and R g are 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, Z and Y are each independently N or CR h (wherein R h =H or is absent), or when R 1 is bonded to Z, Z is C and Y is N or CR h (wherein R h is H), or when R 1 is bonded to Y, Y is C and Z is N or CR h (wherein R h is H), B is an optionally substituted 5- to 7-membered cycloalkyl ring, an optionally substituted 5- to 7-membered heteroaryl ring, or an optionally substituted 5- to 7-membered heterocyclic ring, and ring B is fused to ring C via Y and Z, ULM is a small molecule E3 ubiquitin ligase binding moiety that binds to von Hippel-Lindau E3 ubiquitin ligase. Mode for Carrying Out the Invention

[0013] 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 herein are only for the purpose of describing particular embodiments, and are not intended to limit this disclosure.

[0014] Where a range of values ​​is provided, each intermediate value between the upper and lower limits of that range (such as in the case of a group containing several carbon atoms where the number of carbon atoms each falls within that range is provided), as well as any other stated or intermediate values ​​within that range, are understood to be included in this disclosure up to one-tenth of the lower limit unit, unless otherwise explicitly indicated by the context. These smaller upper and lower limits may be independently included in the smaller range and are also included in this disclosure according to any specifically excluded limits of the range. Where the range includes one or both limits, the range excluding either of the limits that they include is also included in this disclosure.

[0015] The following terms are used to describe this disclosure. If a term is not specifically defined herein, it shall be given the meaning that is recognized in the art by those skilled in the art who apply that term to its use in the context describing this disclosure.

[0016] As used herein and in the appended claims, the articles “a” and “an” refer to one or more (e.g., at least one) grammatical objects of the article, unless otherwise explicitly indicated by the context. For example, “an element” means one or more elements.

[0017] The terms “co-administration,” “co-administration,” or “combination therapy” refer to both co-administration (administering two or more therapeutic agents simultaneously) and time-variable administration (administering one or more therapeutic agents at different times than the administration of additional therapeutic agents), as long as the therapeutic agents are present in the patient at some degree, preferably in effective amounts, at the same time. In certain preferred embodiments, one or more of the compounds described herein are co-administered in combination with at least one additional bioactive agent, particularly an anticancer agent. In particularly preferred embodiments, the co-administration of compounds results in synergistic activity and / or therapy, including anticancer activity.

[0018] As used herein, the term “compound” means, unless otherwise indicated, any specific chemical compound disclosed herein, including tautomers, positional isomers, geometric isomers, and, where applicable, stereoisomers including its optical isomers (enantiomers) and other stereoisomers (diastereomers), and, where applicable in the context, pharmaceutically acceptable salts and derivatives including its prodrug and / or deuterated form. A deuterated small molecule intended is one in which one or more hydrogen atoms contained in the drug molecule are substituted with deuterium.

[0019] Within the scope of its use in this context, the term "compound" generally refers to a single compound, but may also include other compounds such as stereoisomers, positional isomers, and / or optical isomers (including racemic mixtures), as well as specific enantiomers or enantiomerically enriched mixtures of the disclosed compound. The term also, in this context, refers to a prodrug form of a compound modified to facilitate administration and delivery of the compound to the active site. It should be noted that, in particular, numerous substituents and variables associated with the compound are described in this description. Those skilled in the art will understand that the molecules described herein are stable compounds, as generally described below.

[0020] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, thereby targeting those substrate proteins for degradation. For example, E3 ubiquitin ligase proteins, either alone or in combination with E2 ubiquitin conjugate enzymes, induce the binding of ubiquitin to lysine on target proteins, and subsequently target specific protein substrates for degradation by the proteasome. Thus, E3 ubiquitin ligases, either alone or in combination with E2 ubiquitin conjugate enzymes, are involved in the transfer of ubiquitin to targeted proteins. Generally, ubiquitin ligases are involved in polyubiquitination, such as when a second ubiquitin binds to a first ubiquitin, and a third ubiquitin binds to a second ubiquitin, and so on. Polyubiquitination characterizes proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, in which only a single ubiquitin molecule is added to a substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted by the proteasome for degradation, but instead their cellular location or function can be altered, for example, by binding to other proteins that have a domain capable of binding to ubiquitin. To further complicate matters, different lysines on ubiquitin can be targeted by E3 to form chains. The most common lysine is Lys48 on ubiquitin chains, which is used to create polyubiquitin that is recognized by the proteasome.

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

[0022] When a range of carbon atoms such as C1 to C6 is used herein, the entire range, as well as individual numbers of carbon atoms, is included. For example, "C1 to C3" means C 1~ C3, C 1~ C2, C 2~ Includes C3, C1, C2, and C3.

[0023] When used in combination with substituents as defined herein, the term “optionally substituted” means that the substituent may, but is not required to be, substituted with one or more preferred functional groups or other substituents provided herein. For example, the substituent may be a halo, cyano, or C 1~6 Alkyl, C 3~6 Cycloalkyl, C 2~6 Alkenil, C 2~6 Alkinil, Halo (C 1~6 ) Alkyl, C 1~6 Alkoxy, Halo(C) 1~6 Alkoxy), C 1~6 Alkylthio, C 1~6 Alkylamino, NH2, NH(C 1~6 Alkyl), N(C 1~6 Alkyl)2, NH(C 1~6 Alkoxy), N(C 1~6 Alkoxy)2,-C(O)NHC 1~6 Alkyl, -C(O)N(C 1~6 Alkyl)2,-C(O)NH2,-C(O)C 1~6 Alkyl, -C(O)2C 1~6 Alkyl, -NHCO(C 1~6Alkyl), -N(C 1~6 Alkyl)CO(C 1~6 Alkyl), -S(O)C 1~6 Alkyl, -S(O)2C 1~6 The substituents may be optionally substituted with one or more alkyl, oxo, 6-12 membered aryl, benzyl, pyridinyl, pyrazolyl, thiazolyl, isothiazolyl, or other 5-12 membered heteroaryl groups. In some embodiments, each of the above optional substituents is optionally substituted with one or two groups.

[0024] As used herein, the term "cycloalkyl" refers to a 3- to 12-membered cyclic alkyl group, including bridging and spiro rings (e.g., adamantine). Cycloalkyl groups may be fully saturated or partially unsaturated. The term "cycloalkyl" also includes polycondensed ring systems (e.g., ring systems containing 2, 3, or 4 rings), where a monocycloalkyl ring (as defined above) may condense with one or more groups selected from heterocyclic, carbocyclic, aryl, or heteroaryl groups to form a polycondensed ring system. Such polycondensed ring systems may optionally be substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic portion of the polycondensed ring. The rings of a polycondensed ring system may be linked to one another via condensation, spiro, and bridging bonds, where permitted by valence requirements. It should be understood that the individual rings of a polycondensed ring system may be linked to one another in any order. Furthermore, it should be understood that the bonding sites in polycondensed ring systems (as defined above for cycloalkyls) can be at any position on the cycloalkyl ring. Examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclohexyl, cycloheptyl, cyclooctyl, indenyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[4.1.0]heptanyl, spiro[3.3]heptanyl, and spiro[3.4]octanyl. In some embodiments, the cycloalkyls are 3- to 7-membered cycloalkyls.

[0025] As used herein, the term "alkenyl" refers to a C12 compound containing at least one carbon-carbon double bond. 2~ C 12 Refers to an alkyl group. In some embodiments, the alkenyl group is optionally substituted. In some embodiments, the alkenyl group is C 2~ It is a C6 alkenyl.

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

[0027] The terms “alkoxy,” “alkylamino,” and “alkylthio” are used in their conventional sense to refer to alkyl groups bonded to the remainder of a molecule via an oxygen atom (“oxy”), an amino group (“amino”), or a thio group. The term “alkylamino” includes mono-di-alkylamino groups, where the alkyl portions may be the same or different.

[0028] The term "halo" or "halogen" means a fluorine, chlorine, bromine, or iodine atom, either by itself or as part of another substituent.

[0029] The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms are substituted with heteroatoms selected from S, O, P, and N. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkylamines, alkylamides, and alkyl sulfides. This group may be a terminal group or a bridging group. As used herein, a reference to a linear chain in the context of a bridging group refers to a direct chain of atoms linking the two terminal positions of the bridging group.

[0030] As used herein, the term “aryl” refers to a mono-total carbon aromatic ring, or a polycondensed total carbon ring system in which at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 6 to 12 carbon atoms. Aryls include phenyl radicals. Aryls also include polycondensed ring systems (e.g., ring systems containing 2, 3, or 4 rings) having about 9 to 12 carbon atoms, in which at least one ring is aromatic and the other rings may or may not be aromatic. Such polycondensed ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbon ring portion of the polycondensed ring system. The rings of a polycondensed ring system may be connected to each other via condensation, spiro, and bridging bonds, where permitted by valence requirements. It should be understood that, as defined above, the bonding sites of a polycondensed ring system can be at any position on the aromatic ring. Non-exclusive examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, and 1,2,3,4-tetrahydronaphthyl.

[0031] As used herein, the term “heteroaryl” refers to a monoaromatic ring having at least one atom other than carbon in the ring, the atom being selected from the group consisting of oxygen, nitrogen, and sulfur. “Heteroaryl” also includes a polycondensed ring system having at least one such aromatic ring, which is further described below. Thus, “heteroaryl” includes a monoaromatic ring of about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms may also be present in oxidized forms, provided that the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. "Hyperaryl" also includes polycondensed ring systems (e.g., ring systems containing 2, 3, or 4 rings), where, as defined above, a heteroaryl group condenses with one or more rings selected from heteroaryls (e.g., forming naphthilidinyls such as 1,8-naphthilidinyl), heterocycles (e.g., forming 1,2,3,4-tetrahydronaphthilidinyls such as 1,2,3,4-tetrahydro-1,8-naphthilidinyl), carbocyclics (e.g., forming 5,6,7,8-tetrahydroquinolyl), and aryls (e.g., forming indazolyl) to form a polycondensed ring system. Thus, heteroaryls (mono-aromatic or polycondensed ring systems) have about 1 to 20 carbon atoms and about 1 to 6 heteroatoms within the heteroaryl ring. Heteroaryls (mono-aromatic or polycondensed ring systems) may also have about 5 to 12 members or about 5 to 10 members within the heteroaryl ring. A polycondensed ring system may have one or more (e.g., 1, 2, 3, or 4) oxo groups optionally substituted on the carbon or heterocyclic portion of the condensed ring. The rings of a polycondensed ring system may be connected to one another via condensation, spiro, and bridging bonds, where permitted by valence requirements. It should be understood that the individual rings of a polycondensed ring system may be connected to one another in any order. It should also be understood that the bonding points of a polycondensed ring system (as defined above for heteroaryls) can be at any position on the heteroaryl ring.Furthermore, it should be understood that the bonding sites of heteroaryl or heteroaryl polycondensed ring systems can be any suitable atom of the heteroaryl ring, including carbon atoms and heteroatoms (e.g., nitrogen). Examples of heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridadinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinylbenzofuranil, benzimidazolyl, thianaftenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole, and 3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole. In one embodiment, the term “heteroaryl” refers to a monocyclic aromatic ring containing at least one heteroatom. For example, the term includes five-membered and six-membered monocyclic aromatic rings containing one or more heteroatoms. Non-limiting examples of heteroaryls include, but are not limited to, pyridyl, furyl, thiazole, pyrimidine, oxazole, and thiadiazole.

[0032] As used herein, the terms “heterocyclyl” or “heterocycle” refer to a monosaturated or partially unsaturated ring having at least one atom other than carbon in the ring, the atom being selected from the group consisting of oxygen, nitrogen, and sulfur. The term also includes polycondensed ring systems having at least one such saturated or partially unsaturated ring, which are further described below. Thus, the term includes monosaturated or partially unsaturated rings (e.g., 3, 4, 5, 6, or 7-membered rings) having about 1 to 6 carbon atoms and about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The ring may be substituted with one or more (e.g., 1, 2, or 3) oxo groups, and the sulfur and nitrogen atoms may be present in their oxidized forms. Exemplary heterocycles include, but are not limited to, azetidinyl, tetrahydrofuranyl, and piperidinyl. The term “heterocyclic” also includes polycondensed ring systems (e.g., ring systems containing 2, 3, or 4 rings), where monoheterocyclics (as defined above) can condense with one or more groups selected from heterocyclics (e.g., forming 1,8-decahydronaphthilidinyl), carbocyclics (e.g., forming decahydroquinolyl), and aryls to form polycondensed ring systems. Thus, heterocyclics (monosaturated or monopartially unsaturated rings or polycondensed ring systems) have approximately 2 to 20 carbon atoms and 1 to 6 heteroatoms within the heterocyclic portion. Such polycondensed ring systems may optionally be substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic portion of the polycondensed ring. The rings of a polycondensed ring system may be connected to one another via condensation, spiro, and bridging bonds, where permitted by valence requirements. It should be understood that the individual rings of a polycondensed ring system may be connected to one another in any order. Therefore, a heterocycle (monosaturated or monounsaturated or polycondensed ring system) has about 3 to 20 atoms, including about 1 to 6 heteroatoms within the heterocycle system. It should also be understood that the bond sites of a polycondensed ring system (as defined above for heterocyclils) can be at any position on the heterocyclic ring. Furthermore, it should be understood that the bond sites of a heterocycle or a heterocyclic polycondensed ring system can be any suitable atom of the heterocyclic ring, including carbon atoms and heteroatoms (e.g., nitrogen). In one embodiment, the term heterocycle is defined as C 2~20It includes complex algebras. In one embodiment, the term complex algebra is C 2~7 It includes complex algebras. In one embodiment, the term complex algebra is C 2~5 It includes complex algebras. In one embodiment, the term complex algebra is C 2~4Includes heterocycles. Examples of heterocycles include azilidinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydroxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl, dihydroxazolyl, chromanil, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, spiro[cyclopropane-1,1'-isoindlinyl]-3'-one, isoindlinyl-1-one, 2-oxa-6-azaspiro[3,3]heptanyl, imidazolidine-2-one N -Methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, 1,4-dioxane, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, pyran, 3-pyrroline, thiopyran, pyrone, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane, and pyrrolidine-2-one are examples, but are not limited to these. In one embodiment, the term “heterocyclic” refers to a monocyclic saturated or partially unsaturated 3- to 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 heterocyclics include aziridine, azetidine, pyrrolidine, piperidine, piperazine, oxirane, morpholine, and thiomorpholine. As used herein, the term “9-membered or 10-membered heterobicyclic” refers to a partially unsaturated or aromatic fused bicyclic ring system having at least one heteroatom. For example, the term “9-membered or 10-membered heterobicyclic” includes bicyclic ring systems having a benzo ring fused to a 5- or 6-membered saturated, partially unsaturated, or aromatic ring containing one or more heteroatoms.

[0033] As used herein, the term “heteroatom” means including oxygen (O), nitrogen (N), sulfur (S), and silicon (Si). Nitrogen and sulfur may be in oxidized forms where feasible.

[0034] As used herein, the term "chiral" refers to a molecule that has the property of not being able to superimpose its mirror image partner, while the term "achiral" refers to a molecule that can superimpose its mirror image partner.

[0035] As used herein, the term “stereoisomer” refers to compounds that have the same chemical composition but differ in the arrangement of atoms or groups in space, such as enantiomers, diastereomers, and tautomers.

[0036] The terms “patient” or “subject” are used throughout this specification to describe an animal, preferably a human or a domesticated animal, to which a treatment including prophylactic treatment with the compositions of this disclosure is provided. With respect to the treatment of an infection, condition, or disease condition specific to a particular animal, such as a human patient, the term patient refers to that particular animal, including a domesticated animal such as a dog or cat, or livestock such as a horse, cattle, or sheep. Generally, in this disclosure, the term patient refers to a human patient unless otherwise specified or implied by the context of use of the term.

[0037] The term "effective," when used in the context of its intended use, is used to describe the amount of a compound, composition, or component that produces the intended result. The term "effective" encompasses all other terms of effective quantity or effective concentration used otherwise in this application.

[0038] "Pharmacologically acceptable" means that it is approved or can be approved by a federal or state regulatory agency, or a corresponding agency in a country other than the United States, or that it is listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals.

[0039] "Pharmacologically acceptable salt" means a salt of the compound of this disclosure that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. In particular, such salts are nontoxic and may be addition salts of inorganic or organic acids and base addition salts. Specifically, such salts are (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methyl (2) Salts formed with organic acids such as tylbicyclo[2.2.2]-octo-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid; or (2) salts formed when an acidic proton present in the parent compound is substituted with a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; or salts formed when coordinating with an organic base such as ethanolamine, diethanolamine, triethanolamine, or N-methylglucamine. Examples of salts include sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium, and if the compound contains a basic functional group, salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate are further examples.

[0040] "Pharmacologically acceptable excipients" mean substances that are non-toxic, biotolerable, and otherwise biocompatible with respect to administration to a test subject, such as inert substances that are added to a pharmaceutical composition or otherwise used as solvents, carriers, or diluents to facilitate the administration of drugs, and are compatible with them. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0041] A "solvate" refers to a physical bond between a compound of formula I and one or more solvent molecules.

[0042] In one embodiment, “to treat” or “to cure” any disease or disorder means to improve the disease or disorder (e.g., to inhibit or reduce the development of the disease or at least one of its clinical symptoms). In another embodiment, “to treat” or “to cure” means to improve at least one physical parameter, which does not have to be recognizable by the subject. In yet another embodiment, “to treat” or “to cure” means to modulate the disease or disorder physically (e.g., stabilization of recognizable symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, “to treat” or “to cure” means to delay the onset of the disease or disorder.

[0043] In one embodiment, the present disclosure relates to a compound of formula (I),

[0044] [ka] Or the pharmaceutically acceptable salt or solvate thereof, wherein PTM is part of formula IA,

[0045] [ka] During the ceremony, R 1is a covalent bond or a chemical moiety that links PTM and ULM, * is the point of attachment to ULM, n=0~3, each W is independently an optionally substituted -CH2-, -C(O)-, -S(O)-, or -S(O)2-, and when n is 2 or 3, only one W can be -C(O)-, -S(O)-, or -S(O)2-, R c1 and R d1 are each independently H, D, halo, C 1~3 alkyl, C 1~3 haloalkyl, or C 1~4 alkoxyl, R e3 is H, -C(O)R f , or -P(O)(OR g )2, wherein R f and R g are each 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, Z and Y are each independently N or CR h (wherein R h =H or is absent), or when R 1 is bonded to Z, Z is C and Y is N or CR h (wherein R h is H), or when R 1 is bonded to Y, Y is C and Z is N or CR h (wherein R h is H), 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, ring B is condensed to ring C via Y and Z, and ULM is a small molecule E3 ubiquitin ligase binding site that binds to von Hippel-Lindau E3 ubiquitin ligase.

[0046] In some embodiments, the compound of formula I includes a protein-targeting moiety (PTM). In some embodiments, the PTM in the compound of formula I is the portion of formula IA.

[0047] [ka]

[0048] According to this disclosure, B is a ring condensed into the ring "C" via Y and Z.

[0049] In some embodiments, B in formula IA is optionally substituted with a 5- to 7-membered cycloalkyl ring, an optionally substituted 5- to 7-membered heteroaryl ring, or an optionally substituted 5- to 7-membered heterocyclic ring.

[0050] In some embodiments, B in formula IA is a 5- to 7-membered cycloalkyl ring that is optionally substituted.

[0051] In some embodiments, B in formula IA is an optionally substituted 5- to 7-membered cycloalkyl ring, where the optionally substituted substituents are hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, or cyano.

[0052] In some embodiments, B in formula IA is a 5- to 7-membered heteroaryl ring that is optionally substituted.

[0053] In some embodiments, B in formula IA is an optionally substituted 5- to 7-membered heteroaryl ring, the optionally substituted substituent being hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, or cyano.

[0054] In other embodiments, B in formula IA is a 5- to 7-membered complex ring that is optionally substituted.

[0055] In some embodiments, B in formula IA is a 5- to 7-membered heterocyclic ring that is optionally substituted, and the optional substituents are hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, or cyano.

[0056] In some embodiments, n in equation IA is between 0 and 3. In some embodiments, n=0. In other embodiments, n=1. In other embodiments, n=2. In other embodiments, n=3.

[0057] In some embodiments, each W in formula IA is independently -CH2-, -C(O)-, -S(O)-, or -S(O)2- which are substituted by any choice, and when n=2 or 3, only one W can be -C(O)-, -S(O)-, or -S(O)2-.

[0058] In some embodiments, W in formula IA is optionally substituted with -CH2-. In other embodiments, W in formula IA is -CH2-.

[0059] In some embodiments, W in formula IA is optionally substituted with -CH2-, and the optional substituent is an alkyl group, such as methyl (-CH3), ethyl, propyl, etc.

[0060] In other embodiments, W in formula IA is -C(CH3)H-.

[0061] In some embodiments, W in formula IA is -C(O)-.

[0062] In some embodiments, W in Formula IA is -S(O)-.

[0063] In some embodiments, W in Formula IA is optionally substituted -S(O)2-.

[0064] In embodiments of the present disclosure wherein n is 2 or 3, only one W may be -C(O)-, -S(O)-, or -S(O)2-.

[0065] In some aspects, R in Formula IA c1 and R d1 are independently H, D, halo, C 1~3 alkyl, C 1~3 haloalkyl, or C 1~4 alkoxyl.

[0066] In some embodiments, R c1 is H.

[0067] In some embodiments, R c1 is D.

[0068] In some embodiments, R c1 is halo, for example, -F, -Cl, -Br, or -I.

[0069] In some embodiments, R c1 is C 1~3 alkyl, for example, -C1 alkyl, -C2 alkyl, -C3 alkyl, -CH3, -CH2CH3, etc.

[0070] In some embodiments, R c1 is C 1~3 haloalkyl, for example, -C1 haloalkyl, -C2 haloalkyl, -C3 haloalkyl, -CF3, -CH2CF3, etc.

[0071] In some embodiments, R c1 is C 1~4Alkoxyls include, for example, -C1 alkoxyls, -C2 alkoxyls, -C3 alkoxyls, -C4 alkoxyls, -OCH3, -OCH2CH3, etc.

[0072] In some embodiments, R d1 H is H.

[0073] In some embodiments, R d1 It is D.

[0074] In some embodiments, R d1 This is a halo, for example, -F, -Cl, -Br, or -I.

[0075] In some embodiments, R d1 C 1~3 Alkyl groups include, for example, -C1 alkyl, -C2 alkyl, -C3 alkyl, -CH3, -CH2CH3, etc.

[0076] In some embodiments, R d1 C 1~3 Haloalkyls include, for example, -C1 haloalkyl, -C2 haloalkyl, -C3 haloalkyl, -CF3, -CH2CF3, etc.

[0077] In some embodiments, R d1 C 1~4 Alkoxyls include, for example, -C1 alkoxyls, -C2 alkoxyls, -C3 alkoxyls, -C4 alkoxyls, -OCH3, -OCH2CH3, etc.

[0078] In some embodiments, R in formula IA e3 H, -C(O)R f , or -P(O)(OR g )2, and in the formula, R f and R g H and C are independent of each other. 1~4 Alkyl, C 1~4 Substituting alkyl, C 3~8 Cyclecoalkyl, C 3~8 Substituting cyclucoalkyl, C 3~8Heterocycline-alkyl, or C 3~8 It is a substituted heterocycline coalkyl.

[0079] In some embodiments, R e3 H is H.

[0080] In other embodiments, R e3 is -C(O)R f And in the formula, R f H, C 1~4 Alkyl, C 1~4 Substituting alkyl, C 3~8 Cyclecoalkyl, C 3~8 Substituting cyclucoalkyl, C 3~8 Heterocycline-alkyl, or C 3~8 It is a substituted heterocycline coalkyl.

[0081] In other embodiments, R e3 is -C(O)R f And in the formula, R f In other embodiments, R e3 is -C(O)R f And in the formula, R f C 1~4 Alkyl groups include, for example, -C1 alkyl, -C2 alkyl, -C3 alkyl, -C4 alkyl, -CH3, -CH2CH3, etc.

[0082] In other embodiments, R e3 is -C(O)R f And in the formula, R f C 1~4 These are substituted alkyl groups, such as -C1 substituted alkyl groups, -C2 substituted alkyl groups, -C3 substituted alkyl groups, and -C4 substituted alkyl groups.

[0083] In other embodiments, R e3 is -C(O)R f And in the formula, R f C 3~8These are cyclucoalkyls, such as C3 cyclucoalkyls, C4 cyclucoalkyls, C5 cyclucoalkyls, C6 cyclucoalkyls, C7 cyclucoalkyls, and C8 cyclucoalkyls.

[0084] In other embodiments, R e3 is -C(O)R f And in the formula, R f C 3~8 Substitutive cyclucoalkyls include, for example, C3-substituted cyclucoalkyls, C4-substituted cyclucoalkyls, C5-substituted cyclucoalkyls, C6-substituted cyclucoalkyls, C7-substituted cyclucoalkyls, and C8-substituted cyclucoalkyls.

[0085] In other embodiments, R e3 is -C(O)R f And in the formula, R f C 3~8 These are heterocycline coalkyl groups, such as C3 heterocycline coalkyl groups, C4 heterocycline coalkyl groups, C5 heterocycline coalkyl groups, C6 heterocycline coalkyl groups, C7 heterocycline coalkyl groups, and C8 heterocycline coalkyl groups.

[0086] In other embodiments, R e3 is -C(O)R f And in the formula, R f C 3~8 Substituted heterocycline molecules include, for example, C3-substituted heterocycline molecules, C4-substituted heterocycline molecules, C5-substituted heterocycline molecules, C6-substituted heterocycline molecules, C7-substituted heterocycline molecules, and C8-substituted heterocycline molecules.

[0087] In other embodiments, R e3 is -P(O)(OR g )2, and in the formula, each R g H and C are independent of each other. 1~4 Alkyl, C 1~4 Substituting alkyl, C 3~8 Cyclecoalkyl, C 3~8 Substituting cyclucoalkyl, C 3~8 Heterocycline-alkyl, or C3~8 It is a substituted heterocycline coalkyl.

[0088] In other embodiments, R e3 is -P(O)(OR g )2, and in the formula, each R g H is H.

[0089] In other embodiments, R e3 is -P(O)(OR g )2, and in the formula, each R g C 1~4 Alkyl groups include, for example, -C1 alkyl, -C2 alkyl, -C3 alkyl, -C4 alkyl, -CH3, -CH2CH3, etc.

[0090] In other embodiments, R e3 is -P(O)(OR g )2, and in the formula, one of R g H is the other R g C 1~4 Alkyl groups include, for example, -C1 alkyl, -C2 alkyl, -C3 alkyl, -C4 alkyl, -CH3, -CH2CH3, etc.

[0091] In other embodiments, R e3 is -P(O)(OR g )2, and in the formula, at least one R g C 1~4 These are substituted alkyl groups, such as -C1 substituted alkyl groups, -C2 substituted alkyl groups, -C3 substituted alkyl groups, and -C4 substituted alkyl groups.

[0092] In other embodiments, R e3 is -P(O)(OR g )2, and in the formula, at least one R g C 3~8 These are cyclucoalkyls, such as C3 cyclucoalkyls, C4 cyclucoalkyls, C5 cyclucoalkyls, C6 cyclucoalkyls, C7 cyclucoalkyls, and C8 cyclucoalkyls.

[0093] In other embodiments, Re3 is -P(O)(OR g )2, and in the formula, at least one R g C 3~8 Substitutive cyclucoalkyls include, for example, C3-substituted cyclucoalkyls, C4-substituted cyclucoalkyls, C5-substituted cyclucoalkyls, C6-substituted cyclucoalkyls, C7-substituted cyclucoalkyls, and C8-substituted cyclucoalkyls.

[0094] In other embodiments, R e3 is -P(O)(OR g )2, and in the formula, at least one R g C 3~8 These are heterocycline coalkyl groups, such as C3 heterocycline coalkyl groups, C4 heterocycline coalkyl groups, C5 heterocycline coalkyl groups, C6 heterocycline coalkyl groups, C7 heterocycline coalkyl groups, and C8 heterocycline coalkyl groups.

[0095] In other embodiments, R e3 is -P(O)(OR g )2, and in the formula, at least one R g C 3~8 Substituted heterocycline molecules include, for example, C3-substituted heterocycline molecules, C4-substituted heterocycline molecules, C5-substituted heterocycline molecules, C6-substituted heterocycline molecules, C7-substituted heterocycline molecules, and C8-substituted heterocycline molecules.

[0096] In some embodiments, Z and Y in formula IA are independently N or CR. h (In the formula, R h =H) or, if n=1~3, a double bond may be absent so as to form between Z and Y, or R 1 If it is bonded to Z, then Z is C and Y is N or CR h (In the formula, R h (is H) or R 1 When bonded to Y, Y is C, and Z is N or CR. h (In the formula, R h(is H). Examples of these embodiments include:

[0097] [ka] These are some examples.

[0098] In some embodiments, Z is N.

[0099] In other embodiments, Z is CR h And in the formula, R h = H.

[0100] In other embodiments, Z is CR h And in the formula, R h = is absent, and Z is bonded to Y by a double bond.

[0101] In some embodiments, Z is C and R 1 It is connected.

[0102] In some embodiments, Y is N.

[0103] In other embodiments, Y is CR h And in the formula, R h = H.

[0104] In other embodiments, Y is CR h And in the formula, R h = Absent, and Y is bonded to Z by a double bond.

[0105] In some embodiments, Y is C and R 1 It is connected.

[0106] In some embodiments, PTM is part of formula IA, where, * This is the connection point to ULM.

[0107] In some embodiments, R in formula IA 1This is a covalent bond, or a chemical moiety that links PTM and ULM.

[0108] In some embodiments, R in formula IA 1 This is a covalent bond.

[0109] In other embodiments, R in formula IA 1 This is the chemical component that connects PTM and ULM.

[0110] The chemical components used to link the PTM and ULM portions are known in the art. These components are sometimes referred to as "linkers" in the art. In some embodiments, R in formula IA 1 This is a chemical component used to link PTM and ULM, which are known in the relevant art.

[0111] In some embodiments, R in formula IA 1 This is a chemical component used to link PTM and ULM, as described in U.S. Patent Application Publication No. 2019 / 0300521 (which is incorporated herein by reference in its entirety).

[0112] In other embodiments, R in formula IA 1 This is a chemical component used to link PTM and ULM, as described in U.S. Patent Application Publication No. 2019 / 0255066 (which is incorporated herein by reference in its entirety).

[0113] In other embodiments, R in formula IA 1 This is a chemical component used to link PTM and ULM, as described in International Publication No. 2019 / 084030 (which is incorporated herein by reference in its entirety).

[0114] In other embodiments, R in formula IA 1 This is a chemical component used to link PTM and ULM, as described in International Publication No. 2019 / 084026 (which is incorporated herein by reference in its entirety).

[0115] In some embodiments, R in formula IA 1 This is a chemical structural unit represented by the following formula: -(A) q - During the ceremony, q is an integer between 1 and 14. Each A is independent 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 CaseCR 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 , 0 to 6 R 1a and / or R 1bA 3-11 member cycloalkyl group with 0-6 R groups, optionally substituted at the base. 1a and / or R 1b 3-11 member heterocyclines, 0-6 R groups, which are optionally substituted in the base group. 1a and / or R 1b Arials that are optionally substituted in the base, 0 to 6 R 1a and / or R 1b Selected from the group consisting of heteroaryls that are arbitrarily substituted in the base, R 1a , R 1b , R 1c , R 1d , and R 1eThese are, 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 member cycloalkyl, aryl, heteroaryl, 3~11 member heterocyclyl, -O-(3~11 member cycloalkyl), -S-(3~11 member cycloalkyl), NH-(3~11 member cycloalkyl), N(3~11 member cycloalkyl)2, N-(3~11 member 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, -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 R)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, or where the context allows, 1a or R 1b These are linked to or connected to other groups, with 0 to 4 R 1e The group forms a cycloalkyl and / or heterocyclyl moiety which is optionally substituted.

[0116] In these embodiments, q represents the number of connected A units. For example, if q=1, then -(A) q - is -A1-, and when q=2, -(A) q - is -A1-A2-, and when q=3, -(A) q - is -A1-A2-A3-, and when q=4, -(A) q - is -A1-A2-A3-A4-, and when q=5, -(A) q - is -A1-A2-A3-A4-A5-, and when q=6, -(A) q - is -A1-A2-A3-A4-A5-A6-, and if q=7, -(A) q - is -A1-A2-A3-A4-A5-A6-A7-, and when q=8, -(A) q - is -A1-A2-A3-A4-A5-A6-A7-A8-, and if q=9, -(A) q - is -A1-A2-A3-A4-A5-A6-A7-A8-A9-, and when q=10, -(A) q -A1-A2-A3-A4-A5-A6-A7-A8-A9-A 10 - and if q=11, -(A) q -A1-A2-A3-A4-A5-A6-A7-A8-A9-A 10 -A 11 - and if q=12, -(A) q -A1-A2-A3-A4-A5-A6-A7-A8-A9-A 10 -A 11 -A 12 - and if q=13, then -(A) q -A1-A2-A3-A4-A5-A6-A7-A8-A9-A 10 -A 11 -A 12 -A 13 - and if q=14, then -(A) q -A1-A2-A3-A4-A5-A6-A7-A8-A9-A 10 -A 11 -A 12 -A 13 -A14 - is

[0117] In some embodiments, q=4, and R 1 A is the chemical part represented by the formula: -A1-A2-A3-A4-, where A 1-4 Each of these is independently 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 CaseCR 1a R 1b ) 1-4 ,-(CR 1a R 1b ) 1-4 NR(CR 1a R 1b ) 1-4 , selected from the group consisting of 3-11 member cyclucoalkyls, 3-11 member heterocyclines, aryls, and heteroaryls that are optionally substituted, In the formula, R 1a and R 1bThese are, independently, -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 member cycloalkyl, aryl, heteroaryl, 3~11 member heterocyclyl, -O-(3~11 member cycloalkyl), -S-(3~11 member cycloalkyl), NH-(3~11 member cycloalkyl), N(3~11 member cycloalkyl)2, N-(3~11 member Cycloalkyl)(C1~C8alkyl), -OH, -NH2, -SH, -SO2C1~C8alkyl, SO(NH)C1~C8alkyl, P(O)(OC1~C8alkyl)(C1~C8alkyl), -P(O)(OC1~C8alkyl)2, -C≡C-C1~C8alkyl, -C≡CH, -CH=CH(C1~C8alkyl), -C(C1~C8alkyl)=CH(C1~C8alkyl), -C(C1~C8alkyl)=C(C1~C8alkyl)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) Selected from the group consisting of 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, R 1c and R 1d These are C, which is substituted independently by H, D, and an arbitrary choice. 1~4 Alkyl, C 3~8 Cyclecoalkyl, C 3~8Selected from the group consisting of heterocyclic coalkyl, aryl, or heteroaryl.

[0118] In other embodiments, q=3, R 1 A is the chemical part represented by the formula: -A1-A2-A3-, where A 1-3 Each of these is independently 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 CaseCR 1a R 1b ) 1-4 ,-(CR 1a R 1b ) 1-4 NR(CR 1a R 1b ) 1-4 , selected from the group consisting of 3-11 member cycloalkyls, 3-11 member heterocyclines, aryls, and heteroaryls that are optionally substituted, In the formula, R 1a and R 1bThese are, independently, -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 member cycloalkyl, aryl, heteroaryl, 3~11 member heterocyclyl, -O-(3~11 member cycloalkyl), -S-(3~11 member cycloalkyl), NH-(3~11 member cycloalkyl), N(3~11 member cycloalkyl)2, N-(3~11 member Cycloalkyl)(C1~C8alkyl), -OH, -NH2, -SH, -SO2C1~C8alkyl, SO(NH)C1~C8alkyl, P(O)(OC1~C8alkyl)(C1~C8alkyl), -P(O)(OC1~C8alkyl)2, -C≡C-C1~C8alkyl, -C≡CH, -CH=CH(C1~C8alkyl), -C(C1~C8alkyl)=CH(C1~C8alkyl), -C(C1~C8alkyl)=C(C1~C8alkyl)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) Selected from the group consisting of 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, R 1c and R 1d These are C, which is substituted independently by H, D, and an arbitrary choice. 1~4 Alkyl, C 3~8 Cyclecoalkyl, C 3~8Selected from the group consisting of heterocyclic coalkyl, aryl, or heteroaryl.

[0119] In other embodiments, q=2, R 1 A is the chemical part represented by the formula: -A1-A2-, where A 1-2 Each of these is independently 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 CaseCR 1a R 1b ) 1-4 ,-(CR 1a R 1b ) 1-4 NR(CR 1a R 1b ) 1-4 , selected from the group consisting of 3-11 member cycloalkyls, 3-11 member heterocyclines, aryls, and heteroaryls that are optionally substituted, In the formula, R 1a and R 1bThese are, independently, -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 member cycloalkyl, aryl, heteroaryl, 3~11 member heterocyclyl, -O-(3~11 member cycloalkyl), -S-(3~11 member cycloalkyl), NH-(3~11 member cycloalkyl), N(3~11 member cycloalkyl)2, N-(3~11 member Cycloalkyl)(C1~C8alkyl), -OH, -NH2, -SH, -SO2C1~C8alkyl, SO(NH)C1~C8alkyl, P(O)(OC1~C8alkyl)(C1~C8alkyl), -P(O)(OC1~C8alkyl)2, -C≡C-C1~C8alkyl, -C≡CH, -CH=CH(C1~C8alkyl), -C(C1~C8alkyl)=CH(C1~C8alkyl), -C(C1~C8alkyl)=C(C1~C8alkyl)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) Selected from the group consisting of 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, R 1c and R 1d These are C, which is substituted independently by H, D, and an arbitrary choice. 1~4 Alkyl, C 3~8 Cyclecoalkyl, C 3~8Selected from the group consisting of heterocyclic coalkyl, aryl, or heteroaryl.

[0120] In other embodiments, q=1, R 1 A1 is the chemical part represented by the formula -A1-, where A1 is 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 CaseCR 1a R 1b ) 1-4 ,-(CR 1a R 1b ) 1-4 NR(CR 1a R 1b ) 1-4 , selected from the group consisting of 3-11 member cycloalkyls, 3-11 member heterocyclines, aryls, and heteroaryls that are optionally substituted, In the formula, R 1a and R 1bThese are, independently, -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 member cycloalkyl, aryl, heteroaryl, 3~11 member heterocyclyl, -O-(3~11 member cycloalkyl), -S-(3~11 member cycloalkyl), NH-(3~11 member cycloalkyl), N(3~11 member cycloalkyl)2, N-(3~11 member Cycloalkyl)(C1~C8alkyl), -OH, -NH2, -SH, -SO2C1~C8alkyl, SO(NH)C1~C8alkyl, P(O)(OC1~C8alkyl)(C1~C8alkyl), -P(O)(OC1~C8alkyl)2, -C≡C-C1~C8alkyl, -C≡CH, -CH=CH(C1~C8alkyl), -C(C1~C8alkyl)=CH(C1~C8alkyl), -C(C1~C8alkyl)=C(C1~C8alkyl)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) Selected from the group consisting of 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, R 1c and R 1d These are C, which is substituted independently by H, D, and an arbitrary choice. 1~4 Alkyl, C 3~8 Cyclecoalkyl, C 3~8Selected from the group consisting of heterocyclic coalkyl, aryl, or heteroaryl.

[0121] In some embodiments, R 1 This is a covalent bond, with 0 to 6 Rs. 1a and / or R 1b A 3-11 member cycloalkyl group with 0-6 R groups, optionally substituted at the base. 1a and / or R 1b A 3-11 member heterocyclyl, -(CR) is optionally substituted in the base. 1a R 1b ) 1-5 ,-(CR 1a =CR 1b )-,-(CR 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -(In the formula, A is O, S, or NR 1c (is), -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(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-(wherein A is O, S, or NR) 1c (is), -(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-(wherein A is O, S, or NR) 1c (is), -(C≡C)-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -(In the formula, A is O, S, or NR 1c (is), -(C≡C)-(CR 1a R 1b ) 1-5 ,-(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-,-(CR) 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-,-(0-6 R) are optionally substituted in the base. 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -, -(0~6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -,-(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -A-, -(CR1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-A-,-(CR) are optionally substituted in the base. 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 ,-(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-A-(wherein A is O, S, or NR, which are optionally substituted at the base) 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-A-(wherein A is O, S, or NR, which are optionally substituted at the base) 1c (is), -(CR 1a R 1b ) 1-5 -A-(0-6 R's) 1a and / or R 1b (3-11 member cycloalkyl group)-(wherein A is O, S, or NR, where 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 ,-(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base.1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-A-(wherein A is O, S, or NR, which are optionally substituted in the base) 1c (is), -(CR 1a R 1b ) 1-5 -A-(0-6 R's) 1a and / or R 1b (3-11 member heterocyclyl)(wherein A is O, S, or NR, which are optionally substituted in the base) 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(0-6 R's) 1a and / or R 1b (3-11 member cycloalkyl group)-(wherein A is O, S, or NR, where 1c (is), -(CR 1a R 1b ) 1-5 -A-(0-6 R's) 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -A-(wherein each A is independently O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(0-6 R's) 1a and / or R1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein each A is independently O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(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 A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(CO)(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -(CR 1a =CR 1b )-(CR 1a R 1b ) 1-5 -A-(CO)-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -(C≡C)-(CR 1a R 1b ) 1-5 -A-(CO)-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R1b ) 1-5 -A-(CO)-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(CO)-(0~6 R's 1a and / or R 1b (3-11 member cycloalkyl group)-(wherein A is O, S, or NR, where 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(CO)-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(CO)-(0~6 R's 1a and / or R 1b (3-11 member heterocyclyl)(wherein A is O, S, or NR, which are optionally substituted in the base) 1c (is), -(CR 1a R 1b ) 1-5 -A-(0-6 R's) 1a and / or R 1b (3-11 member cycloalkyl)-A-(CO)-(wherein each A is independently O, S, or NR, which are optionally substituted at the base) 1c (is), -(0 to 6 R 1a and / or R 1b (3-11 member cycloalkyl)-CO-(CR) 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -A-(CO)-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(CO)-(wherein A is O, S, or NR) 1c (is), -(0 to 6 R 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -, or -(0 to 6 R 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 That is the case.

[0122] In some embodiments, R 1 is -(0 to 6 R 1a and / or R 1b (3-11 member heterocyclyl)-(CO)-(CR) 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(0 to 6 R 1a and / or R 1b (3-11 member heterocyclyl)-(CO)-A-(CR) 1a R 1b ) 1-5 -(In the formula, A is O, S, or NR 1c (is), -A-(0~6 R 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base.1a R 1b ) 1-5 -A-(wherein each A is independently O, S, or NR) 1c (is), -(0 to 6 R 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(0 to 6 R 1a and / or R 1b (3-11 member heterocyclyl)-(0-6 R) which are optionally substituted in the base 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(0 to 6 R 1a and / or R 1b (3-11 member heterocyclyl)-A-(CR) are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein each A is independently O, S, or NR) 1c (is), -(0 to 4 R 1a and / or R 1b (Heteroaryl)-A-(CR) 1a R 1b ) 1-5 -(In the formula, A is O, S, or NR 1c (is), -(0 to 6 R 1a and / or R 1b (3-11 member cycloalkyl)-(CO)-(CR 1a R 1b ) 1-5-A- (wherein A is O, S, or NR 1c ), -(3- to 11-membered heterocyclyl optionally substituted with 0 to 6 R 1a and / or R 1b groups)-(CR 1a R 1b ) 1-5 -A- (wherein A is O, S, or NR 1c ), -(3- to 11-membered cycloalkyl optionally substituted with 0 to 6 R 1a and / or R 1b groups)-(CO)-A-(CR 1a R 1b ) 1-5 -(wherein A is O, S, or NR 1c ), -(CO)-(3- to 11-membered cycloalkyl optionally substituted with 0 to 6 R 1a and / or R 1b groups)-(CR 1a R 1b ) 1-5 -A- (wherein A is O, S, or NR 1c ).

[0123] In some embodiments, R 1 is -CR 1a =CR 1b -, for example, -CH=CH-, etc.

[0124] In some embodiments, R 1 is -(CR 1a R 1b ) 1-5 , for example, -(CH2) 1-5 -, -CH2-, -CH2CH2CH2-, etc.

[0125] In some embodiments, R 1 is -(CR 1a R 1b ) 1-5 -A- (wherein A is O, S, or NR 1c ), 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-, and the like.

[0126] In another embodiment, R 1 is -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -, wherein A is O, S, or NR 1c , for example, -(CH2) 1-5 -O-(CH2) 1-5 -, -(CH2) 1-5 -S-(CH2) 1-5 -, -(CH2) 1-5 -NH-(CH2) 1-5 -, and the like.

[0127] In some embodiments, R 1 is -(C≡C)-(CR 1a R 1b ) 1-5 , for example, -(C≡C)-(CH2)2-, and the like.

[0128] In some embodiments, R 1 is -(CR 1a R 1b ) 1-5 -(3- to 11-membered cycloalkyl optionally substituted with 0 to 6 R 1a and / or R 1b groups), for example, -CH2-cyclobutyl-, and the like.

[0129] In some embodiments, R 1 is -(CR 1a R 1b ) 1-5 -(3- to 11-membered cycloalkyl optionally substituted with 0 to 6 R 1a and / or R 1b groups)-(CR 1a R 1b ) 1-5 , for example, -CH2-cyclobutyl-CH2-, and the like.

[0130] In some embodiments, R 1 is, -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 For example, -CH2-azetidinyl-CH2-.

[0131] In some embodiments, R 1 is, -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b These are 3- to 11-membered heterocyclyl groups that are optionally substituted at the base, such as -CH2-azetidinyl-.

[0132] In some embodiments, R 1 is -(0 to 6 R 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 - For example, -azetidinyl-CH2-, -pyrrolidonyl-CH2-, -piperidinyl-CH2-, etc.

[0133] In some embodiments, R 1 is, -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c Examples include -CH2-cyclopropyl-CH2-O-.

[0134] In some embodiments, R 1 is -(CR 1a R 1b ) 1-5 -(3- to 11-membered heterocyclyl optionally substituted with 0 to 6 R 1a and / or R 1b groups)-(CR 1a R 1b ) 1-5 -A- wherein A is O, S, or NR 1c , for example, -CH2-piperidinyl-CH2CH2-O-, etc.

[0135] In some embodiments, R 1 is -(CR 1a R 1b ) 1-5 -(3- to 11-membered heterocyclyl optionally substituted with 0 to 6 R 1a and / or R 1b groups)-A- wherein A is O, S, or NR 1c , for example, -CH2-azetidinyl-O-, etc.

[0136] In some embodiments, R 1 is -(CR 1a R 1b ) 1-5 -A-(3- to 11-membered heterocyclyl optionally substituted with 0 to 6 R 1a and / or R 1b groups)- wherein A is O, S, or NR 1c , for example, -CH2-O-azetidinyl-, -CH2-NH-azetidinyl-, etc.

[0137] In other embodiments, R 1 is -(CR 1a R 1b ) 1-5 -A-(3- to 11-membered cycloalkyl optionally substituted with 0 to 6 R 1a and / or R 1b groups)- wherein A is O, S, or NR 1cExamples include -CH2-O-cyclobutylene- and -CH2-NH-cyclobutylene-.

[0138] In some embodiments, R 1 is, -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c For example, -CH2-O-CH2CH2-O-, etc.

[0139] In some embodiments, Y in the compound of formula IA is CR h And in the formula, R h is H, and the compound of formula IA has formula IA-1,

[0140] [ka] In the formula, R c1 , R d1 , R e3 , W, Z, B, n, and R 1 As stated above, equation IA is as follows.

[0141] In some embodiments, n in formula IA-1 is 1.

[0142] In some embodiments of the compound of formula IA-1, at least one W is optionally substituted with -CH2-.

[0143] In some embodiments of the compounds of formula IA-1, at least one W is optionally substituted with -CH2-, and the optional substituents are alkyl, alkoxy, or alkylamino.

[0144] In some embodiments of the compound of formula IA-1, at least one W is -CH2-.

[0145] In some embodiments, W in formula IA-1 is optionally substituted with -CH2-, and the optional substituent is an alkyl group, such as methyl (-CH3), ethyl, propyl, etc.

[0146] In other embodiments, W in formula IA-1 is -CH(CH3)-.

[0147] In some embodiments of the compound of formula IA-1, one W is -C(O)-.

[0148] In some embodiments of the compound of formula IA-1, one W is -S(O)-.

[0149] In some embodiments of the compound of formula IA-1, one W is -S(O)2-.

[0150] In some embodiments, B in formula IA-1 is a 5- to 7-membered cycloalkyl ring that is optionally substituted.

[0151] In some embodiments, B in formula IA-1 is an optionally substituted 5- to 7-membered cycloalkyl ring, where the optionally substituted substituents are hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, or cyano.

[0152] In other embodiments, B in formula IA-1 is a 5- to 7-membered complex ring that is optionally substituted.

[0153] In some embodiments, B in formula IA-1 is a 5- to 7-membered heterocyclic ring that is optionally substituted, and the optional substituents are hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, or cyano.

[0154] In other embodiments, Y in the compound of formula IA is N, and Z is CR. h (In the formula, R h (where is H), the compound of formula IA has formula IA-2,

[0155] [ka] In the formula, R c1 , R d1 , R e3 , W, B, n, and R 1 As stated above, equation IA is as follows.

[0156] In some embodiments, n in formula IA-2 is 1.

[0157] In some embodiments of the compound of formula IA-2, at least one W is optionally substituted with -CH2-.

[0158] In some embodiments of the compounds of formula IA-2, at least one W is optionally substituted with -CH2-, and the optionally substituted substituent is alkyl, alkoxy, or alkylamino.

[0159] In some embodiments of the compound of formula IA-2, at least one W is -CH2-.

[0160] In some embodiments, W in formula IA-2 is optionally substituted with -CH2-, and the optional substituent is an alkyl group, such as methyl (-CH3), ethyl, propyl, etc.

[0161] In other embodiments, W in formula IA-2 is -CH(CH3)-.

[0162] In some embodiments of the compound of formula IA-2, one W is -C(O)-.

[0163] In some embodiments of the compound of formula IA-2, one W is -S(O)-.

[0164] In some embodiments of the compound of formula IA-2, one W is -S(O)2-.

[0165] In other embodiments, B in formula IA-2 is a 5- to 7-membered complex ring that is optionally substituted.

[0166] In some embodiments, B in formula IA-2 is a 5- to 7-membered heterocyclic ring that is optionally substituted, and the optional substituents are hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, or cyano.

[0167] In other embodiments, B in formula IA-2 is a 5- to 7-membered complex ring that is optionally substituted.

[0168] In some embodiments, B in formula IA-2 is an optionally substituted 5- to 7-membered heterocyclic ring, the optionally substituted substituent being hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, or cyano.

[0169] In some embodiments, the compound of formula IA is the compound of formula IA-3,

[0170] [ka] In the formula, m = 1 to 3, X is either -CH2- or NH which is optionally substituted, or R 1 If it is bonded to X, then X is -CH or N, Q is a -CH2-, -(CH2)2-, -C(O)-, -CH2C(O)-, -S(O)-, -S(O)2-, -CH2S(O)2-, or -CH2S(O)- that is substituted by any choice, and R c1 , R d1 , R e3 , W, Z, B, n, and R 1 As stated above, equation IA is as follows.

[0171] In some embodiments of the compound of formula IA-3, n=1. In other embodiments of the compound of formula IA-3, n=2. In yet another embodiment of the compound of formula IA-3, n=3.

[0172] In some embodiments of the compound of formula IA-3, X is -CH-.

[0173] In other embodiments of the compound of formula IA-3, X is NH.

[0174] R 1 In some of these embodiments of the compound of formula IA-3 in which is bonded to X, X is CH.

[0175] R 1 In other embodiments of these compounds of formula IA-3 in which is bonded to X, X is N.

[0176] In some embodiments of the compound of formula IA-3, Q is optionally substituted with -CH2-.

[0177] In some embodiments of the compounds of formula IA-3, Q is optionally substituted -CH2-, and the optional substituent is alkyl, alkoxy, or alkylamino.

[0178] In some embodiments of the compound of formula IA-3, Q is optionally substituted with -(CH2)2-.

[0179] In some embodiments of the compounds of formula IA-3, Q is optionally substituted -(CH2)2-, and the optional substituent is alkyl, alkoxy, or alkylamino.

[0180] In some embodiments of the compound of formula IA-3, Q is -C(O)-.

[0181] In some embodiments of the compound of formula IA-3, Q is optionally substituted with -CH2C(O)-.

[0182] In some embodiments of the compound of formula IA-3, Q is -S(O)-.

[0183] In some embodiments of the compound of formula IA-3, Q is -S(O)2-.

[0184] In some embodiments of the compound of formula IA-3, Q is optionally substituted with -CH2S(O)2-.

[0185] In some embodiments of the compound of formula IA-3, Q is optionally substituted with -CH2S(O)-.

[0186] In some embodiments, the compound of formula IA is the compound of formula IA-4,

[0187] [ka] In the formula, R k =H, D, F, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~4 Alkoxyl, substituted C 1~3 Alkyl, substituted C 1~3 Haloalkyl or substituted C 1~4 It is an alkoxyl, s=0~7, m=1~3, R c1 , R d1 , R e3 , W, n, and R 1 As stated above, equation IA is as follows.

[0188] In some embodiments of the compound of formula IA-4, n=1. In other embodiments of the compound of formula IA-4, n=2. In yet another embodiment of the compound of formula IA-4, n=3.

[0189] In some embodiments of the compound of formula IA-4, m=1. In other embodiments of the compound of formula IA-4, m=2. In yet another embodiment of the compound of formula IA-4, m=3.

[0190] In some embodiments of the compound of formula IA-4, s=0. In some embodiments of the compound of formula IA-4, s=1. In other embodiments of the compound of formula IA-4, s=2. In other embodiments of the compound of formula IA-4, s=3.

[0191] In some embodiments, the compound of formula IA-4 is R k = H.

[0192] In some embodiments, the compound of formula IA-4 is R k = D.

[0193] In some embodiments, the compound of formula IA-4 is R k = F.

[0194] In some embodiments, the compound of formula IA-4 is R k =C 1~3 Alkyl groups include, for example, C1 alkyl, C2 alkyl, C3 alkyl, -CH3, -CH2CH3, etc.

[0195] In some embodiments, the compound of formula IA-4 is R k =C 1~3 Haloalkyls include, for example, C1 haloalkyls, C2 haloalkyls, C3 haloalkyls, -CF3, -CH2CF3, etc.

[0196] In some embodiments, the compound of formula IA-4 is R k =C 1~4 Alkoxyls include, for example, C1 alkoxyls, C2 alkoxyls, C3 alkoxyls, -OCH3, -OCH2CH3, etc.

[0197] In some embodiments, the compound of formula IA-4 is R k = Substituted C 1~3These include alkyl groups, such as substituted C1 alkyl groups, substituted C2 alkyl groups, and substituted C3 alkyl groups.

[0198] In some embodiments, the compound of formula IA-4 is R k = Substituted C 1~3 Haloalkyls include, for example, substituted C1 haloalkyls, substituted C2 haloalkyls, substituted C3 haloalkyls, and so on.

[0199] In some embodiments, the compound of formula IA-4 is R k = Substituted C 1~4 These include alkoxyls, such as substituted C1 alkoxyls, substituted C2 alkoxyls, and substituted C3 alkoxyls.

[0200] In some embodiments, the compound of formula IA is the compound of formula IA-5,

[0201] [ka] In the formula, R k =H, D, F, C 1~3 Alkyl, C 1~3 Haloalkyl, or C 1~4 It is an alkoxyl, m=1~3, s=0~3, R c1 , R d1 , R e3 , W, and R 1 As stated above, equation IA is as follows.

[0202] In some embodiments of the compound of formula IA-5, m=1. In other embodiments of the compound of formula IA-5, m=2. In yet another embodiment of the compound of formula IA-5, m=3.

[0203] In some embodiments of the compound of formula IA-5, s=0. In some embodiments of the compound of formula IA-5, s=1. In other embodiments of the compound of formula IA-5, s=2. In other embodiments of the compound of formula IA-5, s=3.

[0204] In some embodiments, the compound of formula IA-5 is R k = H.

[0205] In some embodiments, the compound of formula IA-5 is R k = D.

[0206] In some embodiments, the compound of formula IA-5 is R k = F.

[0207] In some embodiments, the compound of formula IA-5 is R k =C 1~3 Alkyl groups include, for example, C1 alkyl, C2 alkyl, C3 alkyl, -CH3, -CH2CH3, etc.

[0208] In some embodiments, the compound of formula IA-5 is R k =C 1~3 Haloalkyls include, for example, C1 haloalkyls, C2 haloalkyls, C3 haloalkyls, -CF3, -CH2CF3, etc.

[0209] In some embodiments, the compound of formula IA-5 is R k =H or C 1~4 Alkoxyls include, for example, C1 alkoxyls, C2 alkoxyls, C3 alkoxyls, -OCH3, -OCH2CH3, etc.

[0210] In some embodiments, the compound of formula IA is the compound of formula IA-6,

[0211] [ka] In the formula, R k =H, D, F, C 1~3 Alkyl, C1~3 Haloalkyl, or C 1~4 It is an alkoxyl, s=0~3, R c1 , R d1 , R e3 , and R 1 As stated above, equation IA is as follows.

[0212] In some embodiments of the compound of formula IA-6, s=0. In some embodiments of the compound of formula IA-6, s=1. In other embodiments of the compound of formula IA-6, s=2. In other embodiments of the compound of formula IA-6, s=3.

[0213] In some embodiments of the compound of formula IA-6, R k = H.

[0214] In some embodiments of the compound of formula IA-6, R k = D.

[0215] In some embodiments of the compound of formula IA-6, R k = F.

[0216] In some embodiments of the compound of formula IA-6, R k =C 1~3 Alkyl groups include, for example, C1 alkyl, C2 alkyl, C3 alkyl, -CH3, -CH2CH3, etc.

[0217] In some embodiments of the compound of formula IA-6, R k =C 1~3 Haloalkyls include, for example, C1 haloalkyls, C2 haloalkyls, C3 haloalkyls, -CF3, -CH2CF3, etc.

[0218] In some embodiments of the compound of formula IA-6, R k =H or C 1~4 Alkoxyls include, for example, C1 alkoxyls, C2 alkoxyls, C3 alkoxyls, -OCH3, -OCH2CH3, etc.

[0219] In some embodiments, 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.

[0220] In some embodiments, the ULM is the aforementioned ULM.

[0221] In some embodiments, the ULM is the portion of the ULM described in U.S. Patent Application Publication No. 2019 / 0300521, which is incorporated herein by reference in its entirety.

[0222] In other embodiments, the ULM is the portion of the ULM described in U.S. Patent Application Publication No. 2019 / 0255066, which is incorporated herein by reference in its entirety.

[0223] In other embodiments, the ULM is the ULM portion described in International Publication No. 2019 / 084030 (which is incorporated herein by reference in its entirety).

[0224] In other embodiments, the ULM is the ULM portion described in International Publication No. 2019 / 084026 (which is incorporated herein by reference in its entirety).

[0225] In some embodiments, ULM is a portion having the following formula ULM-I,

[0226] [ka] During the ceremony, ------ is ULM's R 1 This indicates the binding position to the V is either H or F. R 3This is a optionally substituted phenyl, optionally substituted naphthyl, or optionally substituted 5-10 member heteroaryl. R 4 Or R 5 One of these is H, D, haloalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, -COR d CONR e1 R e2 And, R 4 Or R 5 The other of these is either H or D, or R 4 and R 5 These, together with the carbon atom to which they are bonded, form optionally substituted 3- to 5-membered cycloalkyl or heterocycline molecules. W 3 is either an aryl that has been optionally substituted, an aryl that has been optionally substituted, or

[0227] [ka] R 6 and R 7 Independently, are H, D, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted haloalkyl. or R 6 , R 7 , and the carbon atoms to which they are bonded form optionally substituted cycloalkyl or optionally substituted heterocyclines, R 8 This includes a heterocycline that has been optionally substituted, a heteroaryl that has been optionally substituted, an aryl that has been optionally substituted, and -C(O)NR a R b , -NR a R b ,

[0228] [ka] And, R a is selected from H or an optionally substituted alkyl group, R b H, -C(O)- * Selected from, in the formula, * R 1 The bond site is an 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. Each R c These are independently H, halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, or haloalkoxy. Each R d These are independently H, optionally substituted alkyl, or NR e1 R e2 Selected from, Each R e1 and R e2 Independently, H, D, or an alkyl group optionally substituted, or R e1 and R e2 Together with the nitrogen atom to which they are bonded, they form a 4-7 membered heterocycline. p is 0, 1, 2, 3, or 4.

[0229] In some embodiments of ULM-I, V is H.

[0230] In other embodiments of ULM-I, V is F.

[0231] In some embodiments of ULM-I, R 3 is a phenyl compound that is optionally substituted, having the following formula:

[0232] [ka] During the ceremony, R 9 These are H, D, halo, -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 alkoxyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl, R 10 This is H, D, halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, optionally substituted alkoxy, or optionally substituted haloalkoxy. z is 0, 1, 2, 3, or 4.

[0233] R 3 In some embodiments, R is a phenyl compound that is optionally substituted. 10 This is either -F or -OCH3.

[0234] R 3 In some embodiments, R is a phenyl compound that is optionally substituted. 9 It is -CN.

[0235] R 3 In some embodiments, R is a phenyl compound that is optionally substituted. 9 This is a heteroaryl that has been substituted by arbitrary choice.

[0236] R 3 In some embodiments, R is a phenyl compound that is optionally substituted. 9 teeth,

[0237] [ka] These are replaced by arbitrary selections.

[0238] R 3 In other embodiments, R is a phenyl compound that is optionally substituted. 9 teeth,

[0239] [ka] That is the case.

[0240] R 3 In other embodiments, R is a phenyl compound that is optionally substituted. 9 teeth,

[0241] [ka] That is the case.

[0242] In other embodiments, R 3 teeth,

[0243] [ka] That is the case.

[0244] R 3 In some embodiments, R is a phenyl compound that is optionally substituted. 10 z is a hydroxyl, halogen, -NH(C1-C4 alkyl), or C1-C6 alkoxy, and z is 0, 1, 2, 3, or 4.

[0245] In some embodiments of ULM-I, R 4 or R 5One of them is H, and R 4 or R 5 The other of these is an alkyl group that is substituted with H or optionally substituted.

[0246] In other embodiments of ULM-I, R 4 or R 5 One of them is H, and R 4 or R 5 The other of these is a C1-C6 alkyl group that has been optionally substituted.

[0247] In other embodiments of ULM-I, R 4 or R 5 One of them is H, and R 4 or R 5 The other of these is a C1-C6 alkyl group.

[0248] In other embodiments of ULM-I, R 4 or R 5 One of them is H, and R 4 or R 5 The other of these is -CH3.

[0249] In other embodiments of ULM-I, R 4 or R 5 One of them is H, and R 4 or R 5 The other of these is -CH2OH.

[0250] In other embodiments of ULM-I, R 4 and R 5 Both are H.

[0251] In some embodiments of ULM-I, W 3 teeth,

[0252] [ka] That is the case.

[0253] In some embodiments of ULM-I, R 6H is H.

[0254] Some embodiments of ULM-I are R 7 is an alkyl group that is substituted with H or optionally substituted.

[0255] In some embodiments of ULM-I, R 7 H is H.

[0256] In some embodiments of ULM-I, R 7 This is an alkyl group that has been optionally substituted.

[0257] Some embodiments of ULM-I are R 7 These are C1-C6 alkyl groups that are optionally substituted.

[0258] In some embodiments of ULM-I, R 7 These are C1-C6 alkyl groups.

[0259] In some embodiments of ULM-I, R 7 C 1~ C6alk-OH, C 1~ C6alk-NH2, -C 1~ C6alk-CONH- * , or -C 1~ C6alk-NHCO- * And in the formula, * R 1 It is the connection point to [the destination].

[0260] In some embodiments of ULM-I, R 7 It is -t-butyl or -isopropyl.

[0261] In some embodiments of ULM-I, R 7 It is -t-butyl.

[0262] In some embodiments of ULM-I, R 7 It is isopropyl.

[0263] In some embodiments of ULM-I, R 8 , NR a R b That is the case.

[0264] Some embodiments are R a is an alkyl group that is substituted with H or optionally substituted.

[0265] In some embodiments, R a H is H.

[0266] In some embodiments, R b H, optionally substituted alkyl, -C(O)- * And in the formula, * R 1 The bond site is an optionally substituted (cycloalkyl) carbonyl, or an optionally substituted alkylcarbonyl.

[0267] In some embodiments, R b This is an alkylcarbonyl that has been optionally substituted.

[0268] In some embodiments, R b is, -C(O)- * And in the formula, * R 1 It is the connection point to [the destination].

[0269] In some embodiments of ULM-I, R 8 CONR a R b That is the case.

[0270] In some embodiments of ULM-I, R 8 teeth,

[0271] [ka] And in the formula, * R 1 It is the connection point to [the destination].

[0272] In some embodiments of ULM-I, R 8 teeth,

[0273] [ka] And in the formula, * R 1 It is the connection point to [the destination].

[0274] In some embodiments of ULM-I, R 8 teeth,

[0275] [ka] And in the formula, * R 1 It is the connection point to [the destination].

[0276] In some embodiments of ULM-I, R 8 teeth,

[0277] [ka] That is the case.

[0278] In some embodiments, R 8 is, -NH- * And in the formula, * R 1 It is the connection point to [the destination].

[0279] In some embodiments of ULM-I, R 8 This is a heteroaryl that has been substituted by arbitrary choice.

[0280] In some embodiments of ULM-I, R 8 teeth,

[0281] [ka] And in the formula, each R cp is independently a halo, an optionally substituted alkoxy, a cyano, an optionally substituted alkyl, a haloalkyl, or a haloalkoxy, where p is 0, 1, or 2.

[0282] In some embodiments, R 8 teeth,

[0283] [ka] And in the formula, each R c p is independently a halo, an optionally substituted alkoxy, a cyano, an optionally substituted alkyl, a haloalkyl, or a haloalkoxy, where p is 0, 1, or 2.

[0284] In some embodiments, R 8 teeth,

[0285] [ka] And in the formula, * R 1 It is the connection point to [the destination].

[0286] In some embodiments, R 8 teeth,

[0287] [ka] That is the case.

[0288] In some embodiments, R 8 teeth,

[0289] [ka] That is the case.

[0290] In some embodiments, R 8 teeth,

[0291] [ka] That is the case.

[0292] In some embodiments, R 8 teeth,

[0293] [ka] That is the case.

[0294] In some embodiments, R 8 teeth,

[0295] [ka] That is the case.

[0296] In some embodiments, R 8 teeth,

[0297] [ka] That is the case.

[0298] In some embodiments, R 8 teeth,

[0299] [ka] That is the case.

[0300] In some embodiments, R 8 teeth,

[0301] [ka] That is the case.

[0302] In some embodiments, R 8 teeth,

[0303] [ka] That is the case.

[0304] In some embodiments, ULM-I is a compound of the following formula:

[0305] [ka] * ULM's R 1 It is the connection point to [the destination].

[0306] In some embodiments of ULM-IA, ULM-IB, ULM-IC, or ULM-ID, R 9 This is replaced by choice.

[0307] [ka] And, R 10 H, D, hydroxy, halogen, amino C 1~4 Alkyl, or C 1~4 It is an alkyloxy.

[0308] In some embodiments, ULM is a portion having formula ULM-II,

[0309] [ka] During the ceremony, ------ is ULM's R 1 This indicates the binding position to the R 14 These are C1-C6 alkyl groups, such as -CH3, -CH2CH3, -CH(CH3)2, and all other variables have the same range as those described above for ULM-I.

[0310] In some embodiments, R in ULM-II 14 is -CH3. In other embodiments, R in ULM-II 14This is -CH(CH3)2.

[0311] In some embodiments, the compound of formula I has formula IA-7 or IA-8,

[0312] [ka] In the formula, V is either H or F. W is a -CH2-, -C(O)-, -S(O)-, or -S(O)2- which is substituted by any choice, and if n=2 or 3, then only one W can be -C(O)-, -S(O)-, or -S(O)2-. n = 0 to 3, m = 1 to 3, R k =H, D, F, C 1~3 Alkyl, C 1~3 Haloalkyl, or C 1~4 It is an alkoxyl, R c1 and R d1 These are H, D, Halo, and C, independently. 1~3 Alkyl, C 1~3 Haloalkyl, or C 1~4 It is an alkoxyl, R e3 H, -C(O)R f , or -P(O)(OR g )2, and in the formula, R f and R g H and C are independent of each other. 1~4 Alkyl, C 1~4 Substituting alkyl, C 3~8 Cyclecoalkyl, C 3~8 Substituting cyclucoalkyl, C 3~8 Heterocycline-alkyl, or C 3~8 It is a substituted heterocycline coalkyl, R 1 This is a covalent bond, with 0 to 6 Rs. 1a and / or R 1b A 3-11 member cycloalkyl group with 0-6 R groups, optionally substituted at the base. 1a and / or R 1bA 3-11 member heterocyclyl, -(CR) is optionally substituted in the base. 1a R 1b ) 1-5 ,-(CR 1a =CR 1b )-,-(CR 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -(In the formula, A is O, S, or NR 1c (is), -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(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-(wherein A is O, S, or NR) 1c (is), -(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-(wherein A is O, S, or NR) 1c (is), -(C≡C)-(CR 1a R 1b )1-5 -A-(CR 1a R 1b ) 1-5 -(In the formula, A is O, S, or NR 1c (is), -(C≡C)-(CR 1a R 1b ) 1-5 ,-(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-,-(CR) 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-,-(0-6 R) are optionally substituted in the base. 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -, -(0~6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -,-(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-A-,-(CR) 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-A-,-(CR) are optionally substituted in the base. 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5,-(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-A-(wherein A is O, S, or NR, which are optionally substituted at the base) 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(0-6 R's) 1a and / or R 1b (3-11 member cycloalkyl group)-(wherein A is O, S, or NR, where 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 ,-(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-A-(wherein A is O, S, or NR, which are optionally substituted in the base) 1c(is), -(CR 1a R 1b ) 1-5 -A-(0-6 R's) 1a and / or R 1b (3-11 member heterocyclyl)(wherein A is O, S, or NR, which are optionally substituted in the base) 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(0-6 R's) 1a and / or R 1b (3-11 member cycloalkyl group)-(wherein A is O, S, or NR, where 1c (is), -(CR 1a R 1b ) 1-5 -A-(0-6 R's) 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(0-6 R's) 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein each A is independently O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5-A-(wherein A is O, S, or NR) 1c (is), -(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 A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(CO)(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -(CR 1a =CR 1b )-(CR 1a R 1b ) 1-5 -A-(CO)-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -(C≡C)-(CR 1a R 1b ) 1-5 -A-(CO)-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -A-(CO)-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(CO)-(0~6 R's 1a and / or R 1b (3-11 member cycloalkyl group)-(wherein A is O, S, or NR, where 1c(is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(CO)-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(CO)-(0~6 R's 1a and / or R 1b (3-11 member heterocyclyl)(wherein A is O, S, or NR, which are optionally substituted in the base) 1c (is), -(CR 1a R 1b ) 1-5 -A-(0-6 R's) 1a and / or R 1b (3-11 member cycloalkyl)-A-(CO)-(wherein each A is independently O, S, or NR, which are optionally substituted at the base) 1c (is), -(0 to 6 R 1a and / or R 1b (3-11 member cycloalkyl)-CO-(CR) 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b 3-11 are arbitrarily replaced in the base. (CR) 1a R 1b ) 1-5 -A-(CO)-(wherein A is O, S, or NR) 1c (is), -(0 to 6 R 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5-A-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(CO)-(wherein A is O, S, or NR) 1c (is), -(0 to 6 R 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -, or -(0 to 6 R 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 - is R 4 is H, optionally substituted alkyl, optionally substituted C1-C6 alkyl, or -CH3. R 7 is an optionally substituted alkyl, preferably an optionally substituted C1-C6 alkyl, more preferably a C1-C6 alkyl. R 9 These are H, D, halo, -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 alkoxyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl, R 1a , R 1b , R 1c , and R 1eThese are, 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 member cycloalkyl, aryl, heteroaryl, 3~11 member heterocyclyl, -O-(3~11 member cycloalkyl), -S-(3~11 member cycloalkyl), NH-(3~11 member cycloalkyl), N(3~11 member cycloalkyl)2, N-(3~11 member 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, -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 R)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, or where the context allows, 1a Or R 1b These are linked to or connected to other groups, with 0 to 4 R 1e The group forms a cycloalkyl and / or heterocyclyl moiety which is optionally substituted, Each R e1 and R e2 Independently, H, D, or an alkyl group optionally substituted, or R e1 and R e2 These, along with the nitrogen atom to which they are bonded, form 4- to 7-membered heterocyclines.

[0313] In some embodiments, the compound of formula I has the following formula IA-9 or IA-10:

[0314] [ka] In the formula, V is either H or F. W is a -CH2-, -C(O)-, -S(O)-, or -S(O)2- which is substituted by any choice, and if n=2 or 3, then only one W can be -C(O)-, -S(O)-, or -S(O)2-. n = 0 to 3, m = 1 to 3, R k =H, D, F, C 1~3 Alkyl, C 1~3 Haloalkyl, or C 1~4 It is an alkoxyl, s = 0 to 3, R c1 and R d1 These are H, D, Halo, and C, independently. 1~3 Alkyl, C 1~3 Haloalkyl, or C 1~4 It is an alkoxyl, R e3 H, -C(O)R f , or -P(O)(OR g )2, and in the formula, R f and R g H and C are independent of each other. 1~4 Alkyl, C 1~4 Substituting alkyl, C 3~8 Cyclecoalkyl, C 3~8 Substituting cyclucoalkyl, C 3~8 Heterocycline-alkyl, or C 3~8 It is a substituted heterocycline coalkyl, R 1 This is a covalent bond, with 0 to 6 Rs. 1a and / or R 1b A 3-11 member cycloalkyl group with 0-6 R groups, optionally substituted at the base. 1a and / or R 1b A 3-11 member heterocyclyl, -(CR) is optionally substituted in the base. 1a R 1b ) 1-5 ,-(CR 1a =CR 1b )-,-(CR 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -(In the formula, A is O, S, or NR 1c (is), -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(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-(wherein A is O, S, or NR) 1c (is), -(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-(wherein A is O, S, or NR) 1c (is), -(C≡C)-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -(In the formula, A is O, S, or NR 1c (is), -(C≡C)-(CR 1a R 1b ) 1-5 ,-(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-,-(CR) 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-,-(0-6 R) are optionally substituted in the base. 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -, -(0~6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -,-(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-A-,-(CR) 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-A-,-(CR) are optionally substituted in the base. 1a R1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 ,-(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-A-(wherein A is O, S, or NR, which are optionally substituted at the base) 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(0-6 R's) 1a and / or R 1b (3-11 member cycloalkyl group)-(wherein A is O, S, or NR, where 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 ,-(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(CR1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-A-(wherein A is O, S, or NR, which are optionally substituted in the base) 1c (is), -(CR 1a R 1b ) 1-5 -A-(0-6 R's) 1a and / or R 1b (3-11 member heterocyclyl)(wherein A is O, S, or NR, which are optionally substituted in the base) 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(0-6 R's) 1a and / or R 1b (3-11 member cycloalkyl group)-(wherein A is O, S, or NR, where 1c (is), -(CR 1a R 1b ) 1-5 -A-(0-6 R's) 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -A-(wherein each A is independently O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(0-6 R's) 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5-A-(wherein each A is independently O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(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 A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(CO)(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -(CR 1a =CR 1b )-(CR 1a R 1b ) 1-5 -A-(CO)-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -(C≡C)-(CR 1a R 1b ) 1-5 -A-(CO)-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -A-(CO)-(wherein A is O, S, or NR) 1c (is), -(CR 1a R1b ) 1-5 -A-(CO)-(0~6 R's 1a and / or R 1b (3-11 member cycloalkyl group)-(wherein A is O, S, or NR, where 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(CO)-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(CO)-(0~6 R's 1a and / or R 1b (3-11 member heterocyclyl)(wherein A is O, S, or NR, which are optionally substituted in the base) 1c (is), -(CR 1a R 1b ) 1-5 -A-(0-6 R's) 1a and / or R 1b (3-11 member cycloalkyl)-A-(CO)-(wherein each A is independently O, S, or NR, which are optionally substituted at the base) 1c (is), -(0 to 6 R 1a and / or R 1b (3-11 member cycloalkyl)-CO-(CR) 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b Replaced by arbitrary selection in the base (3-11 member cycloalkyl)-(CR 1a R 1b ) 1-5 -A-(CO)-(wherein A is O, S, or NR)1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(CO)-(wherein A is O, S, or NR) 1c (is), -(0 to 6 R 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 - or -(0-6 R 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5- , or R 1 is -(0 to 6 R 1a and / or R 1b (3-11 member heterocyclyl)-(CO)-(CR) 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(0 to 6 R 1a and / or R 1b (3-11 member heterocyclyl)-(CO)-A-(CR) 1a R 1b ) 1-5 -(In the formula, A is O, S, or NR 1c (is), -A-(0~6 R 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein each A is independently O, S, or NR) 1c (is), -(0 to 6 R 1a and / or R 1b(3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(0 to 6 R 1a and / or R 1b (3-11 member heterocyclyl)-(0-6 R) which are optionally substituted in the base 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(0 to 6 R 1a and / or R 1b (3-11 member heterocyclyl)-A-(CR) are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein each A is independently O, S, or NR) 1c (is), -(0 to 4 R 1a and / or R 1b (Heteroaryl)-A-(CR) 1a R 1b ) 1-5 -(In the formula, A is O, S, or NR 1c (is), -(0 to 6 R 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(0 to 6 R 1a and / or R 1b (3-11 member cycloalkyl)-(CO)-(CR 1a R 1b )1-5 -A-(wherein A is O, S, or NR) 1c (is), -(0 to 6 R 1a and / or R 1b (3-11 member cycloalkyl)-(CO)-A-(CR 1a R 1b ) 1-5 -(In the formula, A is O, S, or NR 1c (is), -(CO)-(0~6 R 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c It is. R 4 is H, optionally substituted alkyl, optionally substituted C1-C6 alkyl, or -CH3. R 7 is an optionally substituted alkyl, preferably an optionally substituted C1-C6 alkyl, more preferably a C1-C6 alkyl. R 9 These are H, D, halo, -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 alkoxyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl, R 1a , R 1b , R 1c , and R 1eThese are, 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 member cycloalkyl, aryl, heteroaryl, 3~11 member heterocyclyl, -O-(3~11 member cycloalkyl), -S-(3~11 member cycloalkyl), NH-(3~11 member cycloalkyl), N(3~11 member cycloalkyl)2, N-(3~11 member 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, -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 R)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, or where the context allows, 1a Or R 1b These are linked to or connected to other groups, with 0 to 4 R 1e The group forms a cycloalkyl and / or heterocyclyl moiety which is optionally substituted, Each R e1 and R e2 Independently, H, D, or an alkyl group optionally substituted, or R e1 and R e2 These, along with the nitrogen atom to which they are bonded, form 4- to 7-membered heterocyclines.

[0315] In some embodiments of the compound of formula IA-9 or IA-10, n=1. In other embodiments of the compound of formula IA-9 or IA-10, n=2. In other embodiments of the compound of formula IA-9 or IA-10, n=3.

[0316] In some embodiments of the compound of formula IA-7 or IA-8, m=1. In other embodiments of the compound of formula IA-7 or IA-8, m=2. In other embodiments of the compound of formula IA-7 or IA-8, m=3.

[0317] In some embodiments of the compound of formula IA-9 or IA-10, s=0. In some embodiments of the compound of formula IA-9 or IA-10, s=1. In other embodiments of the compound of formula IA-9 or IA-10, s=2. In other embodiments of the compound of formula IA-9 or IA-10, p=3.

[0318] In some embodiments, compounds of formula IA-9 or IA-10 include R k = H.

[0319] In some embodiments, compounds of formula IA-9 or IA-10 include R k = D.

[0320] In some embodiments, compounds of formula IA-9 or IA-10 include R k = F.

[0321] In some embodiments, compounds of formula IA-9 or IA-10 include R k =C 1~3Alkyl groups include, for example, C1 alkyl, C2 alkyl, C3 alkyl, -CH3, -CH2CH3, etc.

[0322] In some embodiments, compounds of formula IA-9 or IA-10 include R k =C 1~3 Haloalkyls include, for example, C1 haloalkyls, C2 haloalkyls, C3 haloalkyls, -CF3, -CH2CF3, etc.

[0323] In some embodiments, compounds of formula IA-9 or IA-10 include R k =H or C 1~4 Alkoxyls include, for example, C1 alkoxyls, C2 alkoxyls, C3 alkoxyls, -OCH3, -OCH2CH3, etc.

[0324] In some embodiments, compounds of formula IA-9 or IA-10 include R c1 and R d1 These are H, respectively.

[0325] In some embodiments, compounds of formula IA-9 or IA-10 include R e3 = H.

[0326] In some embodiments, compounds of formula IA-9 or IA-10 include R c1 , R d1 , and R e3 These are H, respectively.

[0327] In some embodiments, the compound of formula I is the compound of formula IA-9a or IA-10a,

[0328] [ka] In the formulas, X is either N or CH, and the other variables are as described above for formulas IA-9 and IA-10.

[0329] In some embodiments, the compound of formula I has the following formula IA-11 or IA-12:

[0330] [ka] During the ceremony, W is -CH2- or -CH(CH3-), X is either N or CH. R 1 Covalent bond, -0 to 6 R's 1a and / or R 1b A 3-11 member cycloalkyl group that is optionally substituted at the base. 0 to 6 R's 1a and / or R 1b A 3-11 member heterocycline that is optionally substituted in the base, -(CR 1a R 1b ) 1-5 , -(CR 1a =CR 1b )-, -(CR 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -(In the formula, A is O, S, or NR 1c (is), -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(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-(wherein A is O, S, or NR) 1c (is), -(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-(wherein A is O, S, or NR) 1c (is), -(C≡C)-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -(In the formula, A is O, S, or NR 1c (is), -(C≡C)-(CR 1a R 1b ) 1-5 , -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)- which are optionally substituted at the base, -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)- which are optionally substituted in the base, -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -, -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -, -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-A-(wherein A is O, S, or NR, which are optionally substituted at the base) 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-A-(wherein A is O, S, or NR, which are optionally substituted in the base) 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 , -(CR 1a R 1b ) 1-5-(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-A-(wherein A is O, S, or NR, which are optionally substituted at the base) 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(0-6 R's) 1a and / or R 1b (3-11 member cycloalkyl group)-(wherein A is O, S, or NR, where 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 , -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b(3-11 member heterocyclyl)-A-(wherein A is O, S, or NR, which are optionally substituted in the base) 1c (is), -(CR 1a R 1b ) 1-5 -A-(0-6 R's) 1a and / or R 1b (3-11 member heterocyclyl)(wherein A is O, S, or NR, which are optionally substituted in the base) 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(0-6 R's) 1a and / or R 1b (3-11 member cycloalkyl group)-(wherein A is O, S, or NR, where 1c (is), -(CR 1a R 1b ) 1-5 -A-(0-6 R's) 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -A-(wherein each A is independently O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(0-6 R's) 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5-A-(wherein each A is independently O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(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 (is), -(CR 1a R 1b ) 1-5 -A-(CO)(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -(CR 1a =CR 1b )-(CR 1a R 1b ) 1-5 -A-(CO)-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -(C≡C)-(CR 1a R 1b ) 1-5 -A-(CO)-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R1b ) 1-5 -A-(CO)-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(CO)-(0~6 R's 1a and / or R 1b (3-11 member cycloalkyl group)-(wherein A is O, S, or NR, where 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(CO)-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(CO)-(0~6 R's 1a and / or R 1b (3-11 member heterocyclyl)(wherein A is O, S, or NR, which are optionally substituted in the base) 1c (is), -(CR 1a R 1b ) 1-5 -A-(0-6 R's) 1a and / or R 1b (3-11 member cycloalkyl)-A-(CO)-(wherein each A is independently O, S, or NR, which are optionally substituted at the base) 1c (is), -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-CO-(CR) 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -A-(CO)-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(CO)-(wherein A is O, S, or NR) 1c (is), -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -, -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -, -A-(0-6 R's) 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein each A is independently O, S, or NR) 1c (is), -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b(3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(0-6 R) which are optionally substituted in the base 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-A-(CR) are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein each A is independently O, S, or NR) 1c (is), -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CO)-A-(CR) 1a R 1b ) 1-5 -(In the formula, A is O, S, or NR 1c (is), -(0 to 4 R 1a and / or R 1b (Heteroaryl)-A-(CR) 1a R 1b ) 1-5 -(In the formula, A is O, S, or NR 1c (is), -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CO)-(CR 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c(is), -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CO)-A-(CR 1a R 1b ) 1-5 -(In the formula, A is O, S, or NR 1c (is), or -(CO)-(0~6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is) and R 4 is H, -CH3, or -CH2OH, R 7 This is a C1-C6 alkyl group, preferably -C(CH3)3 or -CH(CH3)2. R 9 is a heteroaryl compound that is optionally substituted with -CN, preferably

[0331] [ka] And, R 1a , R 1b , R 1c , and R 1eThese are, 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 member cycloalkyl, aryl, heteroaryl, 3~11 member heterocyclyl, -O-(3~11 member cycloalkyl), -S-(3~11 member cycloalkyl), NH-(3~11 member cycloalkyl), N(3~11 member cycloalkyl)2, N-(3~11 member 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, -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 R)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, or where the context allows, 1a Or R 1b These are linked to or connected to other groups, with 0 to 4 R 1e The group forms a cycloalkyl and / or heterocyclyl moiety which is optionally substituted.

[0332] In some embodiments, W is -CH2-.

[0333] In some embodiments, X is -N.

[0334] In other embodiments, X is -CH.

[0335] In some embodiments, R 4 It is -CH3.

[0336] In some embodiments, R 7 It is either -C(CH3)3 or -CH(CH3)2.

[0337] In some embodiments, R k This is -CH3, and s=1.

[0338] In some embodiments, s=0.

[0339] In some embodiments, R 9 teeth,

[0340] [ka] That is the case.

[0341] In some embodiments of compounds of formula I, such as formula IA-11 or formula IA-12, R 1 teeth, -(CR 1a R 1b ) 1-5 , -(CR 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5-(In the formula, A is O, S, or NR 1c (is), -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CO)-(CR) 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CO)-A-(CR) 1a R 1b ) 1-5 -(In the formula, A is O, S, or NR 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-A-(wherein A is O, S, or NR, which are optionally substituted at the base) 1c (is), -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 , -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base.1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -A-(0~6 R 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein each A is independently O, S, or NR) 1c (is), -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(0-6 R) which are optionally substituted in the base 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-A-(CR) are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein each A is independently O, S, or NR) 1c (is), -(0 to 6 R's 1a and / or R 1b(3-11 member heterocyclyl)-(CO)-A-(CR) 1a R 1b ) 1-5 -(In the formula, A is O, S, or NR 1c (is), -(0 to 4 R 1a and / or R 1b (Heteroaryl)-A-(CR) 1a R 1b ) 1-5 -(In the formula, A is O, S, or NR 1c (is), -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CO)-(CR 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), -(0 to 6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CO)-A-(CR 1a R 1b ) 1-5 -(In the formula, A is O, S, or NR 1c (is), or -(CO)-(0~6 R's 1a and / or R 1b (3-11 member cycloalkyl)-(CR) 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c It is.

[0342] In some embodiments of the compounds of formula IA-11 or formula IA-12, each R 1a , each R 1b , and each R 1c These are independently H or C1-C6 alkyl groups.

[0343] In some embodiments, compounds of formula IA-11 or formula IA-12 are R1 is, -(CR 1a R 1b ) 1-5 For example, -CH2-, -CH2CH2-, -CH2CH2CH2- 、 Examples include -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, etc.

[0344] In some embodiments, compounds of formula IA-11 or formula IA-12 are R 1 is, -(CR 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c Examples include -CH2-O-, -CH2CH2-O-, -CH2CH2CH2-O-, etc.

[0345] In some embodiments of the compound of formula I, R 1 is, -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -(In the formula, A is O, S, or NR 1c Examples include -CH2CH2CH2-N(CH3)-CH2CH2-, -CH2CH2-N(CH3)-CH2CH2-, and -CH2CH2-O-CH2-.

[0346] In some embodiments of the compound of formula I, R 1 is -(0 to 6 R 1a and / or R 1b (3-11 member heterocyclyl)--(CO)-(CR) 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c Examples include -piperidinyl-(CO)-CH(CH3)-O-, -pyrrolidinyl-(CO)-CH(CH3)-O-, -piperidinyl-(CO)-CH2-O-, and -methylpiperidinyl-(CO)-CH2-O-.

[0347] In some embodiments of the compound of formula I, R 1 is -(0 to 6 R 1a and / or R 1b (3-11 member heterocyclyl)-(CO)-A-(CR) 1a R 1b ) 1-5 -(In the formula, A is O, S, or NR 1c For example, -piperidinyl-(CO)-O-CH2-.

[0348] In some embodiments of the compound of formula I, R 1 is -(0 to 6 R 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c For example, -azabicyclo[3.1.1]heptanyl-CH2CH2-O-, -azapiro[3.3]heptanyl-CH2CH2-O-, -piperidinyl-CH2CH2-O-, -fluoropiperidinyl-CH2CH2-O-, -azepanyl-CH2CH2-O-, -pyrrolidinyl-CH2CH2-O-, -piperidinyl-CH2CH(CH3)-O-, -octahydrocyclopenta[c]pi Examples include loryl-CH2CH2-O-, pyrrolidinyl-CH2CH(CH3)-O-, methylpiperidinyl-CH2CH2-O-, piperidinyl-CH2CH(CH2CH3)-O-, pyrrolidinyl-CH2CH(CH2CH3)-O-, pyrrolidinyl-CH2CH(CH3)-O-, hydroxypyrrolidinyl-CH2CH2-O-, and hydroxypiperidinyl-CH2CH2-O-.

[0349] In some embodiments of the compound of formula I, R 1 is -(0 to 6 R 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5- For example, -piperidinyl-CH2-, -piperidinyl-CH2CH2-, -piperidinyl-CH2CH2CH2-, azetidinyl-CH2CH2CH2-, -aziridinyl-CH2-, -pyrrolidinyl-CH2CH2-, etc.

[0350] In some embodiments of the compound of formula I, R 1 So, -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(0-6 R) which are optionally substituted in the base 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c Examples include -piperidinyl-pyrrolidinyl-CH2CH2-O-, piperidinyl-piperidinyl-CH2CH2-O-, and -pyrrolidinyl-piperidinyl-CH2CH2-O-.

[0351] In some embodiments of the compound of formula I, R 1 So, -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c Examples include -piperidinyl-CH2-piperidinyl-CH2CH2-O-, -piperidinyl-CH2CH2-piperidinyl-CH2CH2-O-, etc.

[0352] In some embodiments of the compound of formula I, R 1 is -(0 to 6 R 1a and / or R 1b(3-11 member cycloalkyl)-A-(CR) 1a R 1b ) 1-5 -(In the formula, each A is independently O, S, or NR 1c For example, -cyclohexyl-N(CH3)-CH2CH2-O-.

[0353] In some embodiments of the compound of formula I, R 1 is -(CO)-(0~6 R 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c For example, -(CO)-piperidinyl-CH2CH2-O-.

[0354] In some embodiments of the compound of formula I, R 1 is, -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -, for example, -CH2-piperidinyl-CH2-, -CH2-piperidinyl-CH2CH2-, -CH2-piperidinyl-CH2CH2CH2-, etc.

[0355] In some embodiments of the compound of formula I, R 1 is, -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein each A is independently O, S, or NR) 1cExamples include -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]octanyl-CH2CH2-O-, -CH2-(dimethyl)piperidinyl-CH2CH2-O-, and -CH2-dihydropiperidinyl-CH2CH2-O-.

[0356] In some embodiments of the compound of formula I, R 1 is, -(CR 1a R 1b ) 1-5 -(0 to 6 R's 1a and / or R 1b (3-11 member heterocyclyl)-A-(wherein A is O, S, or NR, which are optionally substituted in the base) 1c For example, -CH2CH2CH2-pyrrolidinyl-O-.

[0357] In some embodiments of the compound of formula I, R 1 is -(0~4 R 1a and / or R 1b (Heteroaryl)-A-(CR) 1a R 1b ) 1-5 -(In the formula, A is O, S, or NR 1c For example, -pyridinyl-O-CH2-.

[0358] In some embodiments of the compound of formula I, R 1 is -A-(0~6 R 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein each A is independently O, S, or NR) 1c For example, -N(CH3)-piperidinyl-CH2CH2-O-.

[0359] In some embodiments, the compound of formula I has the following formulas: IA-13a, IA-13b, IA-14a, or IA-14b.

[0360] [ka] In the formula, X is either N or CH.

[0361] In some embodiments of compounds of formula IA-13a, IA-13b, IA-14a, or IA-14b, R 1 is -(0 to 6 R 1a and / or R 1b (3-11 member heterocyclyl)-(CO)-(CR) 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c (is), or -(0 to 6 R 1a and / or R 1b (3-11 member heterocyclyl)-(CR) which are optionally substituted in the base. 1a R 1b ) 1-5 -A-(wherein A is O, S, or NR) 1c And, R 1a , R 1b , R 1c , and R 1eThese are, 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 member cycloalkyl, aryl, heteroaryl, 3~11 member heterocyclyl, -O-(3~11 member cycloalkyl), -S-(3~11 member cycloalkyl), NH-(3~11 member cycloalkyl), N(3~11 member cycloalkyl)2, N-(3~11 member 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, -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 R)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, or where the context allows, 1a Or R 1b These are linked to or connected to other groups, with 0 to 4 R 1e The group forms a cycloalkyl and / or heterocyclyl moiety which is optionally substituted.

[0362] In some embodiments of compounds of formula IA-13a, IA-13b, IA-14a, or IA-14b, R 1 (3-11 member heterocyclyl)-(CO)-(CR 1a R 1b ) 1-3 -O-, and in the formula, each R 1a H is H, and each R 1b These are independently H or a -C1~C8 alkyl group, preferably -CH3.

[0363] In other embodiments of compounds of formula IA-13a, IA-13b, IA-14a, or IA-14b, R 1 is -(3-11 member heterocyclyl)-(CR 1a R 1b ) 1-3 -O-, and in the formula, each R 1a H is H, and each R 1b These are independently H or a -C1~C8 alkyl group, preferably -CH3.

[0364] In other embodiments of the compounds of formula IA-13a, IA-13b, IA-14a, or IA-14b, R 1 These include -azabicyclo[3.1.1]heptanyl-CH2CH2-O-, -azapiro[3.3]heptanyl-CH2CH2-O-, -piperidinyl-CH2CH2-O-, -fluoropiperidinyl-CH2CH2-O-, -azepanyl-CH2CH2-O-, -pyrrolidinyl-CH2CH2-O-, -piperidinyl-CH2CH(CH3)-O-, and -octahydrocyclopenta[c]pyrrolyl Examples include -CH2CH2-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-, etc.

[0365] In some embodiments, the compound of formula I has the following formulas: IA-15a, IA-15b, IA-16a, or IA-16b.

[0366] [ka] In the formula, A is O, S, or NR 1c And, R 1a1 is H or a -C1~C8 alkyl group, preferably -CH2CH3 or -CH3. R 1c is -H, or C1-C8 alkyl, preferably -CH3. A 1 is covalent or -(CR 1a R 1b ) 1-3 And, Each R k These are H, D, F, C independently. 1~3 Alkyl, C 1~3 Haloalkyl, C 1~4 Alkoxyl, substituted C 1~3 Alkyl, substituted C 1~3 Haloalkyl or substituted C 1~4 It is an alkoxyl, and its s value is between 0 and 7.

[0367] In some embodiments of the compounds of formula IA-15a, IA-15b, IA-16a, or IA-16b, A is O and R 1a1 The group is a -C1-C8 alkyl group, preferably -CH2CH3, or -CH3.

[0368] In some embodiments of compounds of formula IA-15a, IA-15b, IA-16a, or IA-16b, A 1 This is a covalent bond.

[0369] In some embodiments of compounds of formula IA-15a, IA-15b, IA-16a, or IA-16b, A 1 is, -(CR 1a R 1b ) 1-3 That is the case.

[0370] In some embodiments of the compounds of formula IA-15a, IA-15b, IA-16a, or IA-16b, A is O and R 1a1 It is -CH3.

[0371] In some embodiments of the compounds of formula IA-15a, IA-15b, IA-16a, or IA-16b, s=0.

[0372] In some embodiments of the compounds of formula IA-15a, IA-15b, IA-16a, or IA-16b, s=1, and R k It is -CH3.

[0373] In some embodiments, the compounds disclosed herein include: (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)acetamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)acetamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)acetamide)-3,3-dimethylbutanoyl)-N-(4-(5-methylthiazole-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)acetamide)-3,3-dimethylbutanoyl)-N-(4-(5-methylthiazole-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-methylpiperidine-1-yl)acetamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)acetamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)butanamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)butanamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide, ((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate 2-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-yl)ethyl, ((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-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]pyridazine-8-yl)ethyl, (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)piperidine-1-yl)propanamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)propanamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)isoxazole-5-yl)-3-methylbutanoyl)-5-(((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-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)isoxazole-5-yl)-3-methylbutanoyl)-5-(((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-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)isoxazole-5-yl)-3-methylbutanoyl)-5-(((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-ylisobutyrate, (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)isoxazole-5-yl)-3-methylbutanoyl)-5-(((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-ylisobutyrate, (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)piperidine-1-yl)acetamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)acetamide)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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-azabicyclo[3.1.1]heptan-3-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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-azabicyclo[3.1.1]heptan-3-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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]heptan-2-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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]heptan-2-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)propan-2-yl)oxy)isoxazole-5-yl)3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)propan-2-yl)oxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)propan-2-yl)oxy)isoxazole-5-yl)3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)propan-2-yl)oxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)pyrrolidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)pyrrolidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)pyrrolidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)pyrrolidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)propan-2-yl)oxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)propan-2-yl)oxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)propan-2-yl)oxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)propan-2-yl)oxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)propan-2-yl)oxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)propan-2-yl)oxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)propan-2-yl)oxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)propan-2-yl)oxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)pyrrolidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)pyrrolidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)pyrrolidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)pyrrolidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)pyrrolidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)pyrrolidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)pyrrolidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)pyrrolidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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-methylpiperidine-1-yl)-2-oxoethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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-methylpiperidine-1-yl)-2-oxoethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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-methylpiperidine-1-yl)-2-oxoethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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-methylpiperidine-1-yl)-2-oxoethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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-methylpiperidine-1-yl)-2-oxoethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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-methylpiperidine-1-yl)-2-oxoethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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-methylpiperidine-1-yl)-2-oxoethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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-methylpiperidine-1-yl)-2-oxoethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)pyrrolidine-1-yl)propan-2-yl)oxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)pyrrolidine-1-yl)propan-2-yl)oxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)pyrrolidine-1-yl)propan-2-yl)oxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)pyrrolidine-1-yl)propan-2-yl)oxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)pyrrolidine-1-yl)propan-2-yl)oxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)pyrrolidine-1-yl)propan-2-yl)oxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)pyrrolidine-1-yl)propan-2-yl)oxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)pyrrolidine-1-yl)propan-2-yl)oxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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-methylpiperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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-methylpiperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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-methylpiperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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-methylpiperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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-methylpiperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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-methylpiperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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-methylpiperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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-methylpiperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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-methylpiperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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-methylpiperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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-methylpiperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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-methylpiperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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-methylpiperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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-methylpiperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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-methylpiperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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-methylpiperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)pyrrolidine-1-yl)piperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)pyrrolidine-1-yl)piperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)pyrrolidine-1-yl)piperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)pyrrolidine-1-yl)piperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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)piperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide, (2S,4R)-4-hydroxy-1-((R)-2-(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)piperidine-1-yl)propyl)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide, (2S,4R)-4-hydroxy-1-((R)-2-(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)piperidine-1-yl)propyl)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide, (2S,4R)-4-hydroxy-1-((R)-2-(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)piperidine-1-yl)propyl)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide, or (2S,4R)-4-hydroxy-1-((R)-2-(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)piperidine-1-yl)propyl)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide is included.

[0374] It will be apparent that the compounds of the present invention, including all subgenera described herein, may have multiple stereocenters. As a result, multiple stereoisomers (enantiomers and diastereomers) exist for the compounds (and subgenera described herein). This disclosure intends to encompass each stereoisomer of any compound included herein, as well as mixtures of such stereoisomers.

[0375] The pharmaceutically acceptable salts and solvates of the compounds of this disclosure (including all subgenera described herein) are also within the scope of this disclosure.

[0376] Isotope variants of the compounds disclosed herein (including all subgenera described herein) are also contemplated herein.

[0377] References to formula I or its subgenus (e.g., formulas 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) mean that the specified formula and all applicable subgenus are included.

[0378] For the sake of brevity, certain features of the Invention described herein in the context of separate embodiments may also be provided in combination within a single embodiment. That is, unless obviously incompatible or specifically excluded, each individual embodiment is considered combinatorial with any other embodiment, and such combination is considered a separate embodiment. Conversely, various features of the Invention described in the context of a single embodiment for the sake of brevity may be provided separately or in any partial combination. Embodiments may be described as part of a series of steps or as part of a more general structure, but each such step may also be considered an independent embodiment that is combinatorial with others.

[0379] Pharmaceutical composition and administration method The pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of the compounds of this disclosure as an active ingredient, or to provide pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates, or derivatives thereof. If desired, the pharmaceutical compositions may include pharmaceutically acceptable salts and / or coordination compounds thereof, as well as carriers comprising one or more pharmaceutically acceptable excipients, inert solid diluents and fillers, diluents comprising sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and auxiliaries.

[0380] The pharmaceutical composition in question may be administered alone or in combination with one or more other agents, and is typically administered in the form of a pharmaceutical composition. If desired, one or more compounds of the present invention and other agents may be mixed into a formulation, or both components may be formulated into separate formulations and used together, separately or simultaneously. In some embodiments, the concentrations of one or more compounds provided in the pharmaceutical composition of the present invention are 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%, and 0. Less than 0.8%, 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 any number in the range defined by any two of the above numbers, and any number in the range that includes those numbers).

[0381] In some embodiments, the concentrations of one or more compounds of the present invention are 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%, and 15% in weight ratio (w / w), weight / volume ratio (w / v), or volume ratio (v / v). 0.50%, 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%, 0.0 Greater than 4%, 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 in the range defined by any two of the above numbers, and a number in the range that includes those numbers).

[0382] In some embodiments, the concentration of one or more compounds of the present invention is approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02%, approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, and approximately 0.06% in terms of weight ratio (w / w), weight / volume ratio (w / v), or volume ratio (v / v). The ranges are approximately 25%, 0.07% to 24%, 0.08% to 23%, 0.09% to 22%, 0.1% to 21%, 0.2% to 20%, 0.3% to 19%, 0.4% to 18%, 0.5% to 17%, 0.6% to 16%, 0.7% to 15%, 0.8% to 14%, 0.9% to 12%, and 1% to 10%.

[0383] In some embodiments, the concentration of one or more compounds of the present invention is in the range of about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, and about 0.1% to about 0.9%, in terms of weight ratio (w / w), weight / volume ratio (w / v), or volume ratio (v / v).

[0384] In some embodiments, the amounts of one or more compounds of the present invention are 10g, 9.5g, 9.0g, 8.5g, 8.0g, 7.5g, 7.0g, 6.5g, 6.0g, 5.5g, 5.0g, 4.5g, 4.0g, 3.5g, 3.0g, 2.5g, 2.0g, 1.5g, 1.0g, 0.95g, 0.9g, 0.85g, 0.8g, 0.75g, 0.7g, 0.65g, 0.6g, 0.55g, 0.5g, 0.45g, 0.4g, 0.35g, 0.3g, 0.25g, 0.2g, 0.15g, 0.1g, 0.09g, 0. Less than or equal to 0.8g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g, or 0.0001g (or a number in the range defined by any two of the above numbers, and a number in the range that includes those numbers).

[0385] In some embodiments, the amounts of one or more compounds of the present invention are 0.0001g, 0.0002g, 0.0003g, 0.0004g, 0.0005g, 0.0006g, 0.0007g, 0.0008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.003g, 0.0035g g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.008g, 0. 0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.035g, 0.04g, 0.045g , 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.095g, 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, The values ​​are greater than 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5g, 3g, 3.5g, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g, or 10g (or a number within the range defined by any two of the above numbers, and a number within the range containing those numbers).

[0386] In some embodiments, the amount of one or more compounds of the present invention is in the range of 0.0001 to 10 g, 0.0005 to 9 g, 0.001 to 8 g, 0.005 to 7 g, 0.01 to 6 g, 0.05 to 5 g, 0.1 to 4 g, 0.5 to 4 g, or 1 to 3 g.

[0387] The compounds according to the present invention are effective over a wide dose range. For example, in the treatment of adult humans, doses of 0.01–1000 mg, 0.5–100 mg, 1–50 mg / day, and 5–40 mg / day are examples of doses that may be used. An exemplary dose is 10–30 mg / day. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject being treated, the subject's weight, and the attending physician's preference and experience.

[0388] The pharmaceutical compositions of the present invention typically contain the active ingredient of the present invention (e.g., the compounds of this disclosure), or pharmaceutically acceptable salts and / or coordination compounds thereof, as well as carriers, diluents, sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers and auxiliaries, including but not limited to one or more pharmaceutically acceptable excipients, inert solid diluents and fillers.

[0389] The following describes non-limiting, exemplary pharmaceutical compositions and methods for preparing them.

[0390] Oral pharmaceutical composition. In some embodiments, the present invention provides a pharmaceutical composition for oral administration containing the compound of the present invention and a pharmaceutical excipient suitable for oral administration.

[0391] In some embodiments, the present invention provides a solid pharmaceutical composition for oral administration comprising (i) an effective amount of the compound of the present invention, optionally (ii) an effective amount of a second agent, and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further comprises (iv) an effective amount of a third agent.

[0392] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral administration. Pharmaceutical compositions of the present invention suitable for oral administration may exist as separate dosage forms such as capsules, cachets, or tablets, or as liquids or aerosol sprays containing a predetermined amount of the active ingredient as a powder or granules, in solution, or as a suspension in an aqueous or non-aqueous liquid, oil-in-water emulsion, or water-in-oil liquid emulsion, respectively. Such dosage forms may be prepared by any pharmacist's method, all of which involve a step of binding the active ingredient to a carrier, which constitutes one or more required components. Generally, the composition is prepared by uniformly and closely mixing the active ingredient with a liquid carrier or an ultrafine solid carrier or both, and then, if necessary, forming the product into a desired state. For example, tablets may be prepared by compression or molding with optionally one or more auxiliary components. Compressed tablets can be prepared by compressing a free-flowing active ingredient, such as a powder or granules, in a suitable machine, which may optionally be mixed with excipients, such as binders, lubricants, inert diluents, and / or surfactants or dispersants. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0393] The present invention further encompasses anhydrous pharmaceutical compositions and dosage forms containing active ingredients, since water can accelerate the decomposition of several compounds. For example, in the pharmaceutical field, water (e.g., 5%) may be added as a means of simulating long-term storage to determine properties such as shelf life or the stability of formulations over time. The anhydrous pharmaceutical compositions and dosage forms of the present invention may be prepared using anhydrous or low-moisture-containing ingredients and low-moisture or low-humidity conditions. Pharmaceutical compositions and dosage forms of the present invention containing lactose may be made anhydrous if they are expected to come into substantial contact with moisture and / or humidity during manufacturing, packaging, and / or storage. Anhydrous pharmaceutical compositions may be prepared and stored so as to maintain their anhydrous properties. Therefore, anhydrous compositions may be packaged using materials known to prevent exposure to water, such as those that may be included in suitable formulation kits. Examples of suitable packaging include, but are not limited to, unit dose containers, blister packs, and strip packs, such as airtight foil and plastic.

[0394] The active ingredient can be combined with a pharmaceutical carrier in a homogeneous mixture according to conventional pharmaceutical formulation techniques. The carrier can take a wide variety of forms depending on the desired formulation for administration. When preparing compositions for oral administration, in the case of oral liquid formulations (suspensions, solutions, and elixirs, etc.) or aerosols, any of the usual pharmaceutical culture media, such as water, glycol, oil, alcohol, fragrance additives, preservatives, and colorants, can be used as carriers. In the case of oral solid formulations, carriers such as starch, sugar, microcrystalline cellulose, diluents, granulators, lubricants, binders, and disintegrants can be used without lactose in some embodiments. For example, suitable carriers for solid oral formulations include powders, capsules, and tablets. If desired, tablets can be coated by standard aqueous or non-aqueous techniques.

[0395] Suitable binders for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, acacia, sodium alginate, alginic acid, other alginates, tragacanth powder, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

[0396] Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrate, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0397] A disintegrant may be used in the composition of the present invention to provide a tablet that disintegrates when exposed to an aqueous environment. Too much disintegrant may cause the provided tablet to disintegrate in the container. Too little disintegrant may be insufficient for disintegration to occur, and therefore the release rate and range of the active ingredient from the dosage form may vary. Therefore, to form the dosage forms of the compounds disclosed herein, a sufficient amount of disintegrant, neither too much nor too little, may be used so as not to adversely alter the release of the active ingredient. The amount of disintegrant used may be varied based on the type of formulation and the mode of administration, and may be readily recognizable to those skilled in the art. About 0.5 to about 15% by weight of disintegrant, or about 1 to about 5% by weight of disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polaritrin potassium, sodium glycolate starch, potato starch or tapioca starch, other starches, pregelatinized starch, other starches, clay, other algins, other celluloses, gums, or mixtures thereof.

[0398] Lubricants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, diesel fuel, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurethate, agar, or mixtures thereof. Additional lubricants include, for example, syloid silica gel, synthetic silica aerosol, or mixtures thereof. Lubricants may be added in amounts less than about 1% by weight of the pharmaceutical composition.

[0399] When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredients therein may be combined with various sweeteners or flavoring additives, colorants or dyes, and, if desired, the drugs may be emulsified and / or precipitated with such diluents, such as water, ethanol, propylene glycol, glycerin, and various combinations thereof.

[0400] Tablets may be left uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a long period. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a water or oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0401] Examples of surfactants that can be used to form the pharmaceutical composition and dosage form of the present invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be used, a mixture of lipophilic surfactants may be used, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be used.

[0402] A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while a suitable lipophilic surfactant may generally have an HLB value of about 10 or less. The experimental parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance (HLB) value. Surfactants with lower HLB values ​​are more lipophilic or hydrophobic and have higher solubility in oil, while surfactants with higher HLB values ​​are more hydrophilic and have higher solubility in aqueous solutions.

[0403] Hydrophilic surfactants are generally considered to be compounds with an HLB value greater than approximately 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (e.g., hydrophobic) surfactants are compounds with an HLB value of approximately 10 or less. However, the HLB value of surfactants is a rough guideline commonly used to enable the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0404] Hydrophilic surfactants may be either ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts, fusidicates, 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; lysophospholipids and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium doxate; acyl lactic acid; mono- and diacetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citrate esters of mono- and di-glycerides; and mixtures thereof.

[0405] Within the above group, examples of ionic surfactants include lecithin, lysolecithin, phospholipids, lysophospholipids and their derivatives; carnitine fatty acid ester salts; alkyl sulfate salts; fatty acid salts; sodium doxate; acyl lactic acid; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinyl mono- and di-glycerides; citrate esters of mono- and di-glycerides; and mixtures thereof.

[0406] Ionic surfactants include ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, fatty acid lactic acid esters, stearoyl-2-lactic acid, stear This may include royl lactic acid, succinyl monoglycerides, mono / diacetylated tartrate esters of mono / diglycerides, citrate esters of mono / diglycerides, cholyl sarcosine, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, oleic acid, ricinoleates, linoleates, linolenic acid, stearates, sodium lauryl sulfate, teracecil sulfate, doxate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and salts and mixtures thereof.

[0407] Examples of hydrophilic nonionic surfactants include, but are not limited to, alkyl glucosides, alkyl maltosides, alkyl thioglucosides, lauryl macrogol glycerides, polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers, polyoxyalkylene alkylphenols such as polyethylene glycol alkylphenols, polyoxyalkylene alkylphenol fatty acid esters such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters, polyethylene glycol glycerol fatty acid esters, polyglycerol fatty acid esters, polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters, hydrophilic transesterification products of polyols having at least one member from the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols, polyoxyethylene sterols, derivatives, and analogs thereof, polyoxyethylated vitamins and their derivatives, polyoxyethylene-polyoxypropylene block copolymers, and mixtures thereof, and hydrophilic transesterification products of polyols having at least one member from the group consisting of polyethylene glycol sorbitan fatty acid esters and triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or sugars.

[0408] Other hydrophilic nonionic surfactants include, but are not limited to, PEG-10 lauric acid, PEG-12 lauric acid, PEG-20 lauric acid, PEG-32 lauric acid, PEG-32 dilauric acid, PEG-12 oleic acid, PEG-15 oleic acid, PEG-20 oleic acid, PEG-20 dioleic acid, PEG-32 oleic acid, PEG-200 oleic acid, PEG-400 oleic acid, PEG-15 stearic acid, PEG-32 distearic acid, PEG-40 stearic acid, PEG-100 stearic acid, PEG-20 dilauric acid, PEG-25 glyceryl trioleic acid, PEG-32 dioleic acid, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearic acid, PEG-20 glyceryl oleic acid, PEG-30 glyceryl oleic acid, PEG-30 glyceryl laurate, and PEG-40 glyceryl laurate. Castor Acid, PEG-40 Palm Kernel Oil, PEG-50 Hydrogenated Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil, PEG-40 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Capric Acid / Caprylic Acid Glyceride, PEG-8 Caprylic Acid / Caprylic Acid Glyceride, Polyglyceryl-10 Lauric Acid, PEG-30 Cholesterol, PEG-25 Phytosterol, PEG-30 Soybean Steroid Examples include lorol, PEG-20 trioleic acid, PEG-40 sorbitan oleic acid, PEG-80 sorbitan lauric acid, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinic acid, PEG-24 cholesterol, polyglyceryl-1O oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolauric acid, sucrose monopalmitic acid, PEG-10-100 nonylphenol derivatives, PEG-15-100 octylphenol derivatives, and poloxamer.

[0409] Suitable lipophilic surfactants include, but are not limited to, aliphatic alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of polyols having at least one member from 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 having at least one member from the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0410] In one embodiment, the composition may include a solubilizer to ensure good solubilization and / or dissolution of the compound of the present invention and to minimize precipitation of the compound. This may be particularly important for parenteral use compositions, such as injection compositions. Solubilizers may also be added to increase the solubility of other components, such as hydrophilic drugs and / or surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[0411] Examples of suitable solubilizers include alcohols and polyols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and their isomers, glycerol, pentaerythritol, sorbitol, mannitol, transktol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrin and cyclodextrin derivatives; polyethylene glycol ethers having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycoflor) or methoxyPEG; 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N Examples of amides and other nitrogen-containing compounds include hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, triethyl acetylcitrate, tributyl acetylcitrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and their isomers, δ-valerolactone and their isomers, β-butyrolactone and their isomers; and other solubilizers such as dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water.

[0412] Mixtures of solubilizers may also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, glycoflourol, transktol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycoflourol, and propylene glycol.

[0413] The amount of solubilizer that may be included is not particularly limited. A given amount of solubilizer may be limited to a bioacceptable amount, which may be readily determined by those skilled in the art. Depending on the circumstances, it may be advantageous to include an amount of solubilizer exceeding a bioacceptable amount in order to maximize the concentration of the drug by removing excess solubilizer before providing the composition to the subject using conventional techniques such as distillation or evaporation. Therefore, if present, the solubilizer may be in a weight ratio of 10% by weight, 25% by weight or more, 50% by weight or more, based on the combined weight of the drug and other excipients. If desired, very small amounts of solubilizer, such as 5% or more, 2% or more, 1% or less may also be used. Typically, the solubilizer may be present in amounts of about 1% by weight or more to about 100% by weight, more typically about 5% by weight or more to about 25% by weight.

[0414] The composition may further contain one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, tack reducers, defoamers, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, isotonic agents, flavoring agents, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0415] In addition, acids or bases may be added to the composition to accelerate processing, improve 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, and tris(hydroxymethyl)aminomethane (Tris). Bases are also preferred, which are salts of pharmaceutically acceptable acids such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid. Salts of polyhydrogen acids such as sodium phosphate, disodium phosphate, and sodium dihydrogen phosphate may also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation such as ammonium, alkali metals, or alkaline earth metals. Examples include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0416] 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, and phosphoric acid. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid.

[0417] Pharmaceutical composition for injection. In some embodiments, the present invention provides an injectable pharmaceutical composition comprising the compound of the present invention and a pharmaceutical excipient suitable for injection. The components and amounts of the drug in the composition are as described herein.

[0418] Forms into which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oily suspensions or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical solvents.

[0419] Aqueous solutions in physiological saline are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be used. Adequate fluidity can be maintained to preserve the particle size required in the case of dispersion, for example by using a coating such as lecithin, and by using surfactants. Prevention of microbial action can be achieved by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and thimerosal.

[0420] A sterile injectable solution is prepared by compounding the required amount of the compound of the present invention in a suitable solvent with various other components as listed above, as needed, and then sterile filtering. Generally, dispersions are prepared by compounding various sterile active ingredients into a non-reproductive container containing a basic dispersion medium and other required components from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, particular preferred preparation methods are vacuum drying and freeze-drying techniques, which result in a powder of the active ingredient and any additional desired components from its previously sterile filtered solution.

[0421] Pharmaceutical compositions for local (e.g., transdermal) delivery. In some embodiments, the present invention provides a pharmaceutical composition for transdermal delivery, comprising a compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery.

[0422] The compositions of the present invention can be formulated into solid, semi-solid, or liquid formulations suitable for topical or local administration, such as gels, water-soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, and dimethyl sulfoxide (DMSO) solutions. Generally, high-density carriers can provide areas with prolonged exposure to the active ingredient. In contrast, solution formulations may result in more immediate exposure of the active ingredient to a selected area.

[0423] The pharmaceutical composition may also contain a suitable solid or gel-phase carrier or excipient, which is a compound that enables increased penetration of therapeutic molecules across the skin's stratum corneum permeability barrier or facilitates their delivery. Many of these penetration-enhancing molecules are well known to those trained in the art of topical formulations.

[0424] Examples of such carriers and excipients include, but are not limited to, polymers such as humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidone, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starch, cellulose derivatives, gelatin, and polyethylene glycol.

[0425] Another exemplary formulation for use in the method of the present invention utilizes a transdermal delivery device ("patch"). Such a transdermal patch may be used to deliver a controlled amount of the compound of the present invention in a continuous or discontinuous infusion, with or without another agent.

[0426] The construction and use of transdermal patches for drug delivery are well known in the art. See U.S. Patents 5,023,252, 4,992,445, and 5,001,139. ​​Such patches may be constructed for continuous, pulsed, or as needed drug delivery.

[0427] Inhalation pharmaceutical composition. Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, compositions are administered orally or via nasal respiration for topical or systemic effects. Preferably, compositions in pharmaceutically acceptable solvents may be atomized using an inert gas. Atomized solutions may be inhaled directly from a spraying device, or the spraying device may be attached to a face mask tent or an intermittent positive pressure respirator. Solutions, suspensions, or powder compositions may be administered preferably orally or nasally from a device that delivers the formulation in an appropriate manner.

[0428] Other pharmaceutical compositions. The pharmaceutical composition may also be prepared from the compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intranasal administration. The preparation of such pharmaceutical compositions is well known in the art. For example, Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002, Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990, Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw. See Hill, 20037ybg, Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001, Remington Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins, 2000, Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999).

[0429] The compounds or pharmaceutical compositions of the present invention may be administered by any method that enables delivery of the compounds to the site of action. These methods include oral, intraduodenal, parenteral infusion (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal, or injectable), local administration (e.g., perdermal application), rectal administration, local delivery via catheter or stent, or inhalation. The compounds may also be administered intrafatally or intrathecally.

[0430] In some embodiments, the compounds or pharmaceutical compositions of the present invention are administered by intravenous injection.

[0431] The amount of compound administered depends on the subject being treated, the severity of the disorder or condition, the administration rate, the compound's configuration, and the prescribing physician's discretion. However, the effective dose is in the range of about 0.001 to about 100 mg per kg of body weight per day, preferably about 1 to about 35 mg / kg / day, either as a single dose or in divided doses. For a 70 kg person, this is about 0.05 to 7 g / day, preferably about 0.05 to about 2.5 g / day. In some cases, dose levels below the lower limit of the above range may be adequate, but in other cases, such higher doses may still be used without causing any adverse side effects, for example, by dividing such higher doses into several smaller doses to be administered throughout the day.

[0432] In some embodiments, the compounds of the present invention are administered as a single dose. Typically, such administration may be carried out by infusion, such as intravenous infusion, to rapidly deliver the drug. However, other routes may be used as appropriate. Single doses of the compounds of the present invention may also be used for the treatment of acute conditions.

[0433] In some embodiments, the compounds of the present invention are administered multiple times. Administration may be about once, twice, three times, four times, five times, six times, or more than six times per day. Administration may 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 agent are administered together about once to about six times per day. In another embodiment, administration of the compounds of the present invention and the agent continues for less than about seven days. In yet another embodiment, administration continues for about six, ten, fourteen, or twenty-eight days, two months, six months, or more than one year. In some cases, continuous administration is achieved and maintained as needed.

[0434] Administration of the compounds of the present invention may be continued for as long as necessary. In some embodiments, the compounds of the present invention are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the compounds of the present invention are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the compounds of the present invention are administered over a long period of time during the course of treatment, for example, for the treatment of chronic effects.

[0435] The effective amount of the compound of the present invention may be administered in single or multiple doses by intra-arterial infusion, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, local, or inhalation, by any of the acceptable modes of administration of drugs having similar efficacy, including rectal, buccal, nasal, and transdermal routes.

[0436] The compositions of the present invention may also be delivered, for example, via impregnated or coated devices such as stents, or via arterially inserted cylindrical polymers. Such delivery methods can help prevent or improve restenosis after procedures such as balloon angioplasty. Although not limited to theory, the compounds of the present invention can slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall that contribute to restenosis. The compounds of the present invention may be delivered, for example, by local delivery from the stent wall, from stent grafts, from implants, or from the stent cover or sheath. In some embodiments, the compounds of the present invention are mixed with a matrix. Such a matrix may be a polymer matrix and can serve to bind the compounds to the stent. Suitable polymer matrices for such use include, for example, lactone polyesters or copolyesters such as polylactide, polycaprolactone glycoside, polyorthoester, polyanhydride, polyamino acid, polysaccharide, polyphosphazene, and poly(ether-ester) copolymer (e.g., PEO-PLLA); and fluorinated polymers such as polydimethylsiloxane, poly(ethylene-vinyl acetate), acrylate polymers or copolymers (e.g., polyhydroxyethyl methyl methacrylate, polyvinylpyrrolidone), polytetrafluoroethylene, and cellulose esters. Suitable matrices may be non-degradable or may degrade over time, releasing the compound or compound. The compounds of the present invention may be applied to the surface of the stent by various methods such as dip coating / spin coating, spray coating, dip coating, and / or brush coating. The compounds may be applied in a solvent, and the solvent may be evaporated to form a layer of the compound on the stent. Alternatively, the compounds may be placed in the body of the stent or graft, for example, in microchannels or micropores. When implanted, the compounds diffuse out of the stent body and come into contact with the arterial wall. Such stents may 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, followed by evaporation of the solvent.Excess drug on the stent surface may be removed by additional, simple solvent washing. In further embodiments, the compounds of the present invention may be covalently bonded to the stent or graft. A biodegradable covalent linker may be used to facilitate the release of the compounds of the present invention. Any biodegradable bond, such as an ester, amide, or anhydride bond, may be used. The compounds of the present invention may be administered intravascularly through a balloon used during angioplasty. Extravascular administration of the compounds of the formulation of the present invention via the pericardium and adventitia may also be performed to reduce restenosis.

[0437] Various stent devices that may be used as described are disclosed in the following references, all of which are incorporated herein by reference: U.S. Patent Nos. 5,451,233, 5,040,548, 5,061,273, 5,496,346, 5,292,331, 5,674,278, 3,657,744, 4,739,762, 5,195,984, 5,292,331, 5,674,278, 5,879,382, and 6,344,053.

[0438] The compounds of the present invention may be administered in doses. It is well known in the art that individualization of the administration regimen is necessary for optimal treatment due to inter-subject variability in the pharmacokinetics of the compounds. The administration of the compounds of the present invention can be determined by routine experiments in light of this disclosure.

[0439] The compound of the present invention is administered in a composition containing one or more agents, the agents having a shorter half-life than the unit dose form of the compound of the present invention, and the compound of the present invention may be appropriately adjusted. The pharmaceutical composition may be in a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained-release formulations, solutions, or suspensions; or in a form suitable for parenteral infusion, such as a sterile solution, suspension, or emulsion; or in a form suitable for topical administration, such as an ointment or cream; or in a form suitable for rectal administration, such as a suppository. The pharmaceutical composition may also be in a unit dose form suitable for single-dose administration of a precise dose. The pharmaceutical composition will contain a conventional pharmaceutical carrier or excipient and the compound according to the present invention as an active ingredient. In addition, it may contain other drugs or pharmaceuticals, carriers, adjuvants, etc. Examples of parenteral administration forms include solutions or suspensions of the active compound in sterile aqueous solutions, such as aqueous propylene glycol or dextrose solutions. Such administration forms can be suitably buffered if desired.

[0440] How to use This method typically involves administering a therapeutically effective dose of the compound of the present invention to a subject. The therapeutically effective dose of the target combination of compounds may vary depending on the intended use (in vitro or intra vivo) or the subject and disease state being treated, such as the subject's weight and age, the severity of the disease state, and the mode of administration, which can be readily determined by those skilled in the art. The term also applies to doses that induce a specific response in target cells, such as a reduction in the proliferation or downregulation of the activity of a target protein. A specific dose may vary depending on the specific compound selected, the subsequent administration regimen, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system on which it is carried.

[0441] In certain embodiments, the present invention provides a pharmaceutical composition comprising a bispecific compound or a pharmaceutically acceptable salt thereof.

[0442] In certain embodiments, the present invention provides a pharmaceutical composition comprising a bispecific compound for use in the degradation of target proteins within cells.

[0443] In a particular embodiment, a method for degrading a target protein, comprising administering a therapeutically effective amount of a bispecific compound or a pharmaceutically acceptable salt thereof to a cell, wherein the compound is effective in degrading the target protein.

[0444] In certain embodiments, the present invention provides a pharmaceutical composition comprising a bispecific compound for use in the treatment or prevention of a disease or disorder in which SMARCA2 and / or SMARCA4 play a role.

[0445] In certain embodiments, the present invention provides a pharmaceutical composition comprising a bispecific compound for use in the treatment or prevention of a disease or disorder in which SWI / SNF mutations play a role.

[0446] In certain embodiments, the target proteins are SMARCA2, SMARCA4, and / or PB1.

[0447] In a particular embodiment, the target protein complex is SWI / SNF in the cell.

[0448] In certain embodiments, diseases or disorders that depend on SMARCA2 or SMARCA4 include cancer.

[0449] In certain embodiments, diseases or disorders that depend on the SWI / SNF complex include cancer.

[0450] Exemplary cancers that can be treated with this compound alone or in combination with at least one additional anticancer agent include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma; cancers of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovaries, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas, particularly Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, and myosarcoma. Sarcomas include sarcomas, peripheral neuroepitheliomas, synovial sarcomas, gliomas, astrocytomas, oligodendrogliomas, ependymomas, glioblastomas, neuroblastomas, gangliomas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningiosarcomas, neurofibromas, and schwannomas; intestinal cancers, breast cancers, prostate cancers, cervical cancers, uterine cancers, lung cancers, ovarian cancers, testicular cancers, thyroid cancers, astrocytomas, esophageal cancers, pancreatic cancers, stomach cancers, liver cancers, colon cancers, melanomas; carcinosarcomas, Hodgkin's disease, Wilms' tumors, and teratomas. Further cancers that can be treated with the compounds of this 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-cell ALL, precursor B-cell lymphoma, large B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, and Philadelphia chromosome-positive CML.

[0451] In certain further embodiments, the cancer is SMARCA2 and / or SMARAC4-dependent cancer.

[0452] In some embodiments, the cancer has a SMARCA4 mutation.

[0453] In certain embodiments, the present invention provides a pharmaceutical composition comprising a bispecific compound for use when the disease or disorder dependent on SMARCA2 and / or SMARCA4 is cancer.

[0454] The compounds of this disclosure, and pharmaceutical compositions containing them, may be administered alone or in combination with medical therapies to treat any of the diseases described. Examples of medical therapies include surgery and radiotherapy (e.g., gamma irradiation, neutron radiation therapy, electron beam radiation therapy, proton therapy, close-range radiotherapy, whole-body radioisotopes).

[0455] In other embodiments, the compounds of this disclosure, and pharmaceutical compositions comprising them, may be administered alone or in combination with one or more other agents to treat any of the diseases described.

[0456] Alternatively, the compounds of this disclosure, and pharmaceutical compositions containing them, can be administered in combination with nuclear receptor agonists.

[0457] Alternatively, the compounds of this disclosure, and pharmaceutical compositions containing them, can be administered in combination with a nuclear receptor antagonist.

[0458] Alternatively, the compounds of this disclosure, and pharmaceutical compositions containing them, may be administered in combination with antiproliferative agents.

[0459] Combination therapy For the treatment of cancer and other proliferative disorders, the compounds of the present invention can be used in combination with chemotherapeutic agents, nuclear receptor agonists or antagonists, or other antiproliferative agents. The compounds of the present invention can also be used in combination with surgery or radiotherapy, such as gamma irradiation, neutron radiation therapy, electron beam radiation therapy, proton therapy, close-range radiotherapy, or whole-body radioisotopes. Examples of suitable chemotherapy drugs include avalerix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, all-trans retinoic acid, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bendamustine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous injection, busulfan oral, carsterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daltevarin sodium, dasatinib, and daunol. Bicin, decitabine, denileukin, denileukin difutitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alpha-2a, irinotecan, lapatinib tosylate(ditosylate), lenalidomide, letrozole, leucovorin, lubrolide acetate, levamisole, lomustine, mechloretamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone fenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panobinostat, panitumumab, pegasparagase, pegfilgrastim, pemetrexed disodium, pentostatin, pipo Examples include any of the following: broman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib malate, tamoxifen, temozolomide, teniposide, testactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, barrubicin, vinblastine, vincristine, vinorelbine, vorinstat, and zoledronate. In some embodiments, the compounds of the present invention can be used in combination with therapeutic agents that target epigenetic regulators. Examples of epigenetic regulators include bromodomain inhibitors, histone lysine methyltransferase inhibitors, histone arginine methyltransferase inhibitors, histone demethylase inhibitors, histone deacetylase inhibitors, histone acetylase inhibitors, and DNA methyltransferase inhibitors. An example of a histone deacetylase inhibitor is vorinostat. Examples of histone arginine methyltransferase inhibitors include inhibitors of protein arginine methyltransferases (PRMTs) such as PRMT5, PRMT1, and PRMT4. Examples of DNA methyltransferase inhibitors include inhibitors of DNMT1 and DNMT3. For the treatment of cancer and other proliferative disorders, 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-delta 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 extraterminal family member (BET) inhibitors, BTK inhibitors (e.g., ibrutinib, acalabrutinib), BCL2 inhibitors (e.g., venetoclax), BCL2 family bilayer inhibitors (e.g., BCL2 / BCLxL), PARP inhibitors, FLT3 inhibitors, or LSD1 inhibitors.

[0460] In some embodiments, the inhibitor of the immune checkpoint molecule is a PD-1 inhibitor, for example, 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 a PD-L1 inhibitor, for example, 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 a CTLA-4 inhibitor, for example, an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab.

[0461] 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).

[0462] The compounds of the present invention include, but are not limited to, those shown in Table 1.

[0463] [Table 1-1]

[0464] [Table 1-2] [Examples]

[0465] The compounds of the present invention can be prepared using the general procedure described below.

[0466] [ka]

[0467] Compounds of formula (IA) can be synthesized, for example, using the sequence shown in scheme A. N Compound A-3 is obtained by coupling compound A-1 and A-2 via an Ar reaction or Pd-catalyzed cross-coupling. The following intramolecular S NCyclization product A-4 can be obtained by Ar reaction or amide formation. A-6 can be obtained by introducing a protecting group to facilitate organometallic addition of Ar, using a suitable boronic acid or ester, or other Pd-catalyzed reaction, for example, via Suzuki conditions (in the presence of a palladium catalyst, such as, but not limited to, tetrakis(triphenylphosphine)palladium(O) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), which are complexes of dichloromethane and a base (e.g., a carbonate base). Suitable synthetic method (S N 2 reactions, S N This includes, but is not limited to, Ar reactions, reductive amination, Buchwald reaction, amide formation, Mitsunobu reaction, and olefin metathesis, using R 1 By introducing [a specific component], compound A-7 can be obtained. The protecting group on A-7 can be removed using standard conditions to obtain compound IA.

[0468] [ka]

[0469] Compounds of formula I-8 can be synthesized, for example, using the sequence shown in scheme I. In the presence of a base (e.g., Cs2CO3, NaHCO3, DIPEA), the S between I-1 and compound I-2 is synthesized at high temperature. NAlcohol I-3 can be obtained by the Ar reaction. Compound I-4 can be obtained by converting the hydroxyl group of I-3 to a leaving group (LG) under appropriate conditions (including, but not limited to, treatment with SOCl2, CBr4 / PPh3, or MsCl / Et3N). Compound I-5 can be obtained by treating I-4 with NaN3. Compound I-6 can be obtained by reducing the azide group of compound I-5 to the corresponding amine using PPh3 or Pd / H2, followed by intramolecular cyclization. Alternatively, compound I-6 may be obtained by treating compound I-4 with ammonium hydroxide at high temperature. Compound I-7 can be obtained by protecting the -NH group with a suitable group (e.g., Boc, SEM, Bn, etc.), which can then be converted to compound I-8 under standard Suzuki conditions (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), which are complexes of dichloromethane and a base (e.g., a carbonate base)) using a suitable boronic acid or ester (e.g., 2-hydroxyphenylboronic acid).

[0470] [ka]

[0471] Compounds of formula II-5 can be synthesized, for example, using the sequence shown in scheme II. Suitable synthesis method (amide formation, S N This includes, but is not limited to, two reactions such as reductive amination. For example, compound II-2 can be obtained by coupling compound II-1 and R1 using RG1 (RG1 is a leaving group such as a bromide and is substituted with the amine of II-1). Compound I-8 can be synthesized using an appropriate synthetic method (S N 2 reactions, S NCompound II-4 can be obtained by introduction using methods such as, but not limited to, Ar reactions, reductive amination, Buchwald reaction, amide formation, Mitsunobu reaction, and olefin metathesis. Alternatively, the synthesis of II-4 can be achieved by coupling I-8 with R1, followed by the introduction of II-1 using the appropriate synthetic method described above. By removing the protecting group, the compound of formula II-5 can be obtained.

[0472] [ka]

[0473] The compounds of formula III-5 can be synthesized, for example, using the sequence shown in scheme III. Suitable synthesis method (S N 2 reactions, S N Compound III-2 can be obtained by coupling compound III-1 and R1 using a suitable synthetic method (S) such as the Ar reaction or the Mitsunobu reaction. Compound I-8 can be synthesized using a suitable synthetic method (S N 2 reactions, S N Compound III-4 can be obtained by introduction using methods such as, but not limited to, Ar reactions, reductive amination, Buchwald reaction, amide formation, Mitsunobu reaction, and olefin metathesis. Alternatively, the synthesis of III-4 can be achieved by coupling I-8 with R1, followed by the introduction of intermediate III-1 using the appropriate synthetic method described above. By removing the protecting group, the compound of formula III-5 can be obtained.

[0474] [ka]

[0475] The compound of formula IV-4 can be synthesized, for example, using the sequence shown in scheme IV. Amide IV-2 is obtained by coupling compound IV-1 with an acid under standard amide coupling conditions (e.g., treatment with a suitable base such as DIPEA or Et3N, and in the presence of a coupling agent such as HATU, HOBt, or PyBOP). The compound of formula IV-4 can be obtained by nucleophilic addition of compound IV-3 under basic conditions (e.g., in the presence of a carbonate base, DIPEA, Et3N, etc.).

[0476] [ka]

[0477] An exemplary synthesis for preparing the compound of formula V-4 is shown in Scheme V. Ether V-2 can be obtained by nucleophilic substitution of a haloalkyl acid with compound V-1 under basic conditions (e.g., in the presence of a carbonate base, DIPEA, Et3N, etc.). Amide V-3 can be obtained by coupling amine IV-3 with carboxylic acid V-2 under standard amide coupling conditions (e.g., treatment with a suitable base such as DIPEA or trimethylamine, and in the presence of a coupling agent such as HATU, HOBt, or PyBOP). The compound of formula V-4 can be obtained by removing the protecting group using appropriate conditions.

[0478] [ka]

[0479] An exemplary synthesis for preparing the compound of formula VI-3 is shown in Scheme VI. Ether VI-1 can be obtained by nucleophilic substitution of the alkyl dihalide with alcohol V-1 under basic conditions (e.g., in the presence of a carbonate base, DIPEA, Et3N, etc.). Compound VI-2 can be obtained by nucleophilic substitution of VI-1, where LG2 is a leaving group such as a halo, with amine IV-3 under basic conditions (e.g., in the presence of a carbonate base, DIPEA, Et3N, etc.). By removing appropriate protecting group conditions, the compound of formula VI-3 can be obtained.

[0480] [ka]

[0481] Compounds of formula VII-9 can be synthesized, for example, using the sequence shown in scheme VII. Amide VII-3 can be obtained by coupling amine VII-1 with carboxylic acid VII-2 under standard amide coupling conditions (treatment with a suitable base such as, but not limited to, DIPEA or trimethylamine, and in the presence of a coupling agent such as HATU, HOBt, or PyBOP). Ether VII-4 can be obtained by nucleophilic substitution of VII-3 with an alkyl dihalide under basic conditions (e.g., in the presence of a carbonate base, DIPEA, Et3N, etc.). Compound VII-5 can be obtained by a second nucleophilic substitution of VII-4, where LG2 is a halo, with IV-3 under basic conditions (e.g., in the presence of a carbonate base, DIPEA, Et3N, etc.). Compound VII-6 can be obtained by hydrolysis of the t-butyl ester using appropriate conditions. Amide VII-8 can be obtained by coupling 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). Deprotection of VII-8 can yield the compound of formula VII-9.

[0482] [ka]

[0483] Compounds of formula VIII-5 can be synthesized, for example, using the sequence shown in scheme VIII. Compound VIII-2 can be obtained by reductive amination between compound IV-3 and VIII-1. Compound VIII-5 can be obtained by removal of the protecting group, followed by nucleophilic substitution of VIII-4, where LG is a halo, with VIII-3 under basic conditions (e.g., in the presence of a carbonate base, DIPEA, Et3N, etc.).

[0484] [ka]

[0485] Compound IX-3 can be synthesized as shown in scheme IX. Compound IX-2 can be obtained by nucleophilic substitution of IX-1, where LG is a halo, with VIII-3 under basic conditions (e.g., in the presence of a carbonate base, DIPEA, Et3N, etc.). Compound IX-3 can be obtained by removal of the protecting group.

[0486] Synthesis of intermediates Intermediate 1: 2-(6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (Intermediate 1).

[0487] [ka]

[0488] Step a. Synthesis of 4-(3,6-dichloropyridazin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl (3). To a solution of penta-4-in-1-ol (5.0 g, 59.4 mmol) and 3,4-dihydro-2H-pyran (10 g, 118 mmol) in DCM (10 mL), pyridine (9.6 mL, 118 mmol) and TsOH (22.6 g, 118 mmol) were added at 0°C, and the mixture was stirred at 25°C for 16 hours. The residue was washed with water (20 mL x 2) and then with saturated brine solution (20 mL). The organic matter was then separated, dried (MgSO4), and concentrated to dryness. Next, the crude product was purified by silica gel column chromatography (100-200 mesh size, elution with PE:SiO = 20:1) to obtain 4-(3,6-dichloropyridazin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl(3) (2.0 g, 11.8 mmol, yield 20%) as a white oily substance. 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).

[0489] Step b. Synthesis of 3-(bromomethyl)-4-(3,6-dichloropyridazin-4-yl)piperazine-1-carboxylate tert-butyl(4). Triphenylphosphine (5.9 mg, 22.6 mmol) was added to a solution of N-bromosuccinimide (2.0 g, 11.3 mmol) and 4-(3,6-dichloropyridazin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl (3) (4.1 g, 11.3 mmol) in DCM (50 mL). The mixture was stirred at 25°C for 16 hours. The mixture was washed with water (50 mL), concentrated under vacuum, and the residue was purified by silica gel chromatography (PE:SiO=2:1) ​​to obtain 3-(bromomethyl)-4-(3,6-dichloropyridazin-4-yl)piperazine-1-carboxylate tert-butyl (4) (3.2 g, 7.5 mmol, yield 66.5%) as a white solid. LCMS C 14 H 19Calculated value of BrCl2N4O2: 426.1; Measured value: LCMS[M+H]: 427.1.

[0490] Step c. Synthesis of 2-chloro-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carboxylate tert-butyl(5). A mixed solution of 3-(bromomethyl)-4-(3,6-dichloropyridazin-4-yl)piperazin-1-carboxylate tert-butyl(4) (1.1 g, 2.6 mmol) in a solution of ammonium hydroxide (20 mL, 240 mmol) and 1,4-dioxane (20 mL) was stirred in an autoclave at 80°C for 48 hours. The reaction product was concentrated under vacuum, and the residue was purified by silica gel chromatography (SiO2, 200-300 mesh, PE:siRNA=1:2) to obtain 2-chloro-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate tert-butyl(5) (330 mg, 1.0 mmol, yield 39%) as a white solid. LCMS C 14 H 20 Calculated value of ClN5O2: 325.8; Measured value: LCMS[M+H]: 326.2.

[0491] Step d. Synthesis of 2-chloro-6a,7,9,10-tetrahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate di-tert-butyl(6). To a solution of di-tert-butyl dicarbonate (401 mg, 1.8 mmol) and 2-chloro-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate tert-butyl(5) (200 mg, 0.61 mmol) in DCM (5 mL), DMAP (62 mg, 0.61 mmol) and triethylamine (0.4 mL, 2.5 mmol) were added at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by silica gel chromatography (PE:SiO = 20:1~5:1) to obtain 2-chloro-6a,7,9,10-tetrahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate di-tert-butyl(6) (130 mg, 0.31 mmol, yield 50%) as a white solid. LCMS C 19 H 28 Calculated value of ClN5O4: 425.9; Measured value of LCMS[M+H]: 426.3.

[0492] Step e. Synthesis of 2-(2-hydroxyphenyl)-6a,7,9,10-tetrahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate di-tert-butyl(8). Potassium carbonate (84.4 mg, 0.61 mmol) and Pd(dppf)2Cl2 (24.9 mg, 0.03 mmol) were added at room temperature to a solution of 2-chloro-6a,7,9,10-tetrahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate di-tert-butyl(6) (130 mg, 0.31 mmol) and 2-hydroxyphenylboronic acid (42 mg, 0.31 mmol) in 1,4-dioxane (5 mL). The mixture was stirred at 105°C for 18 hours. The reaction product was concentrated, and the residue was purified by gel chromatography (SiO2, 200-300 mesh, PE:SiO=1:2) to obtain 2-(2-hydroxyphenyl)-6a,7,9,10-tetrahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate di-tert-butyl(8) (180 mg, 0.41 mmol, yield 99.9%) as a white solid. LCMS C 25 H 33 Calculated value of N5O5: 483.5; Measured value: LCMS[M+H]: 484.3.

[0493] Step f. Synthesis of 2-(6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (intermediate 1). A solution of 2-(2-hydroxyphenyl)-6a,7,9,10-tetrahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate di-tert-butyl(8) (180 mg, 0.37 mmol) and TFA (1.5 mL, 19.6 mmol) in DCM (1.5 mL) was stirred at 25°C for 2 hours. The mixed solution was concentrated under vacuum, the residue was added to 5 mL of water, the pH was adjusted to >7 with NaHCO3(aq), extracted with ethyl acetate, and filtered to obtain 2-(6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (intermediate 1) (70 mg, 0.24 mmol, yield 64%) as a white solid. LCMS C 15 H 17 Calculated value of N5O: 283.3; Measured value: LCMS[M+H]: 284.1. 1 H NMR(400 MHz,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),3.4 0-3.44(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).

[0494] Alternative synthesis of 2-chloro-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate tert-butyl(5).

[0495] [ka]

[0496] Step a. Synthesis of 3-(azidomethyl)-4-(3,6-dichloropyridazin-4-yl)piperazine-1-carboxylate tert-butyl (15). To a solution of 3-(bromomethyl)-4-(3,6-dichloropyridazin-4-yl)piperazine-1-carboxylate tert-butyl(4) (2.7 g, 6.3 mmol) in DMF (15 mL), sodium azide (535 mg, 8.2 mmol) and 18-crown-6 (1.6 g, 6.3 mmol) were added, and the mixture was stirred at 45°C for 18 hours. Water (50 mL) and ethyl acetate (60 mL) were added to the mixture. Extraction was performed with ethyl acetate (60 mL x 2). The ethyl acetate layer was concentrated under vacuum to obtain 3-(azidomethyl)-4-(3,6-dichloropyridazin-4-yl)piperazine-1-carboxylate tert-butyl(15) (2.0 g, 5.2 mmol, yield 81%) as a yellow oil. LCMS C 14 H 19 C l2 Calculated value of N7O2: 387.1; Measured value: LCMS[M+H]: 388.1.

[0497] Step b. Synthesis of 2-chloro-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate tert-butyl(5). To a solution of tert-butyl(15)(15) (2.0 g, 5.2 mmol) in DMF (10 mL), triphenylphosphine (1.4 g, 5.2 mmol) was added, and the mixture was stirred at 45°C for 18 hours. The solution was added to a mixture of water (60 mL) and ethyl acetate (50 mL), extracted with ethyl acetate (60 mL x 2), concentrated under vacuum, and the residue was purified by gel silica chromatography (SiO2, 200-300 mesh, PE:ethyl acetate 10:1-1:2) to obtain 2-chloro-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate tert-butyl(5) (1500 mg, 4.6 mmol, yield 89%) as a yellow solid. LCMS C 14 H 20 Calculated value of ClN5O2: 325.1; Measured value: LCMS[M+H]: 326.2.

[0498] 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)pyrrolidine-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazole-3-yl)oxy)acetic acid (intermediate 2).

[0499] [ka]

[0500] 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)pyrrolidine-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazole-3-yl)oxy)ethyl(10). (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methyl-1λ) in THF (15 mL) 3 ,3λ 2 To a solution of -thiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (9) (prepared using the procedure described in U.S. Patent Application Publication No. 2020 / 0038378, 150 mg, 0.24 mmol) and 2-hydroxyethyl acetate (51 mg, 0.48 mmol), PPh3 (128 mg, 0.48 mmol) and DIAD (0.15 mL, 0.48 mmol) were added at 25°C, and the mixture was stirred at 25°C for 2 hours. The mixture was concentrated, and the residue was purified by preparative TLC (PE:SiO=1:1) to obtain 2-((5-(1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1-(4-(4-methyl-1λ 3 ,3λ 2Thiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazole-3-yl)oxy)ethyl)(10) (90 mg, 0.13 mmol, yield 53%) was obtained as a yellow oily substance. LCMS C 35 H 50 Calculated value of N4O7SSi: 698.32; Measured value: LCMS[M+H]: 699.4.

[0501] Step b. 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)pyrrolidine-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazole-3-yl)oxy)acetic acid (intermediate 2). 2-((5-(1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1-(4-(4-methyl-1λ) in a mixture of NaOH (10.2 mg, 0.3 mmol), water (6.0 mL), and methanol (12.0 mL). 3 ,3λ 2 A solution of thiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazole-3-yl)oxy)ethyl)(10) (90 mg, 0.13 mmol) is prepared in 25 o The mixture was stirred in C for 2 hours. The pH of the mixture was adjusted to 4-5 with HCl (1N), extracted with SiO (40 mL x 2), concentrated, and the residue was purified by preparative TLC (PE:SiO = 1:1) to obtain 2-((5-(1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1-(4-(4-methyl-1λ 3 ,3λ 2Thiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazole-3-yl)oxy)acetic acid (intermediate 2) (45 mg, 0.06 mmol, yield 52%) was obtained as a yellow oily substance. LCMS C 33 H 46 Calculated value of N4O7SSi: 670.29; Measured value: LCMS[M+H]: 671.4.

[0502] 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)pyrrolidine-2-carboxamide (intermediate 3).

[0503] [ka] (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methyl-1λ) in DMF (3 mL) 3 ,3λ 2The mixture was added to a solution of -thiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (9) (prepared using the procedure described in U.S. Patent Application Publication No. 2020 / 0038378, 100 mg, 0.16 mmol) and 1,2-dibromoethane (45 mg, 0.24 mmol), and the mixture was stirred with NaHCO3 (60 mg, 0.67 mmol) at 25°C and the mixture at 30°C for 16 hours. The reaction product was dissolved in ELISA (20 mL), and the organic matter was washed with water (20 mL x 3) and brine (20 mL). The organic matter was then separated, dried (MgSO4), and concentrated to dryness. Next, the crude product was purified by preparative TLC (siRNA:PE=2:1) ​​to obtain (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 (intermediate 3) (50 mg, 0.07 mmol, yield 51%) was obtained as a sticky, colorless solid. LCMS C 33 H 47 Calculated value of BrN4O5SSi: 718.2; Measured value: LCMS[M+H]: 719.3.

[0504] Intermediate 4. (2S,4R)-1-((R)-2-(3-(2-bromoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Intermediate 4).

[0505] [ka] (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 (intermediate 3) was separated by preparative HPLC (eluting with 50%~90% H2O:CH3CN (0.1% FA)) to (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 (30 mg, 0.04 mmol, yield 25%) was obtained as a white solid. LCMS C 33 H 47 Calculated value of BrN4O5SSi: 718.2; Measured value: LCMS[M+H]: 719.2.

[0506] Intermediate 5. (2S,4R)-1-((S)-2-(2-chloroacetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methyl-1λ 3 ,3λ 2 -Thiazol-5-yl)benzyl)pyrroridine-2-carboxamide (intermediate 5).

[0507] [ka] (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methyl-1λ) in DCM (15 mL) 3 ,3λ 2To a solution of (2S,4R)-1-((S)-2-(2-chloroacetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methyl-1λ), eluate 2-(2S,4R)-1-((S)-2-(2-chloroacetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methyl-1λ), eluate 2-(2-chloroacetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methyl-1λ), eluate 2-(2-chloroacetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methyl-1λ) 3 ,3λ 2 -Thiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (intermediate 5). (520 mg, 0.98 mmol, yield 84%) was obtained as a yellow solid. LCMS C 24 H 31 Calculated value of ClN4O4S: 507.0; Measured value: LCMS [m / z]: 507.2.

[0508] The intermediates listed in the table below were prepared using the same method used to prepare intermediate 5.

[0509] [Table 2]

[0510] Intermediate 8.2-(8-(piperidine-4-ylmethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (intermediate 8).

[0511] [ka]

[0512] Step a. Synthesis of 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 tert-butyl(16). NaBH(OAc)3 (0.12 ml, 0.59 mmol) was added at room temperature to a solution of 1-Boc-piperidine-4-carboxyaldehyde (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 (intermediate 1) (56 mg, 0.20 mmol) in DCM (10 ml). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated under vacuum and purified by preparative TLC (MeOH:DCM = 1:10) to obtain 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 tert-butyl(16) (60 mg, 0.12 mmol, yield 63%) as a yellow solid. LCMS C 26 H 36 Calculated value for N6O3: 480.3; Measured value: LCMS[m / z]=481.3.

[0513] Step b. Synthesis of 2-(8-(piperidine-4-ylmethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (intermediate 8). To a solution of 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 tert-butyl(16) (60 mg, 0.12 mmol) in methanol (3 ml), HCl (0.07 ml, 0.37 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum to obtain 2-(8-(piperidine-4-ylmethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (intermediate 8) (60 mg, 0.11 mmol, yield 91%) as a solid. LCMS C 21 H 28 Calculated value for N6O: 380.2; Measured value: LCMS[m / z]=381.2.

[0514] The intermediates in the table below were prepared using appropriate starting materials and the same method used to prepare intermediate 8.

[0515] [Table 3-1]

[0516] [Table 3-2]

[0517] [Table 3-3]

[0518] Intermediate 9: (R)-2-(6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-2-yl)phenol (Intermediate 9)

[0519] [ka]

[0520] Step 1: Synthesis of (R)-4-(3,6-dichloropyridazin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl.

[0521] [ka] To a solution of 3,4,6-trichloropyridazine (5.7 g, 31.1 mmol) in DMF (24 mL), N,N-diisopropylethylamine (5.9 mL, 34.2 mmol) and (R)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl (7.1 g, 32.8 mmol) were added. The reaction mixture was stirred overnight at 80°C. The reaction mixture was cooled to 45°C, and water (17 mL) was slowly added. The resulting clear solution was stirred at 35°C for 30 minutes until a precipitate formed. Another volume of water (23 mL) was slowly added, and the mixture was stirred at 0°C for a further 1 hour. The mixture was filtered, the resulting solid was washed with water, and dried under vacuum to obtain (R)-4-(3,6-dichloropyridazine-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl (8.5 g, yield 75%) as an off-white solid. LCMS C 14 H 21 Cl2N4O3[M+H] + Calculated m / z value: 363.1; measured value: 363.1.

[0522] Step 2: Synthesis of (R)-3-(azidomethyl)-4-(3,6-dichloropyridazin-4-yl)piperazine-1-carboxylate tert-butyl.

[0523] [ka] To a solution of (R)-4-(3,6-dichloropyridazin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl (5.45 g, 15 mmol) and triphenylphosphine (4.7 g, 18 mmol) in THF (150 mL), diisopropyl azodicarboxylate (3.5 mL, 18 mmol) and DPPA (3.9 mL, 18 mmol) were added at 0°C. The reaction mixture was then stirred overnight at room temperature. The reaction mixture was cooled to 0°C, quenched with water, and extracted with ethyl acetate. The combined organic layers were washed with brine and water, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain crude (R)-3-(azidomethyl)-4-(3,6-dichloropyridazin-4-yl)piperazine-1-carboxylate tert-butyl (19.4 g, 100% yield), which was used without further purification. We assumed a yield of 100% and a purity of 30%. LCMS C 14 H 20 Cl2N7O2[M+H] + Calculated m / z value: 388.1; measured value: 388.0.

[0524] Step 3: Synthesis of (S)-2-chloro-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate tert-butyl.

[0525] [ka] Triphenylphosphine (4.9 g, 18.8 mmol) was added to a stirred solution of crude (R)-3-(azidomethyl)-4-(3,6-dichloropyridazin-4-yl)piperazine-1-carboxylate tert-butyl (30% purity, 20.3 g, 15.7 mmol) in THF (200 mL). The resulting solution was stirred at 60°C for 3 hours. Water (20 mL) and N,N-diisopropylethylamine (8.2 mL, 47.1 mmol) were added sequentially. After 20 hours, the reaction mixture was diluted with ELISA (100 mL) and water (100 mL). The aqueous layer was separated and extracted with ELISA. 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% ethyl acetate / hexane) to obtain (S)-2-chloro-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate tert-butyl (3.1 g, yield 60%) as an off-white solid. LCMS C 14 H 21 ClN5O2[M+H] + Calculated m / z value: 326.1; measured value: 326.2.

[0526] Step 4: Synthesis of (R)-2-chloro-6a,7,9,10-tetrahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate di-tert-butyl.

[0527] [ka] 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-carboxylate tert-butyl (3.1 g, 9.5 mmol) in DCM (120 mL), di-tert-butyl dicarbonate (6.2 g, 28.6 mmol) and 4-(dimethylamino)pyridine (1.2 g, 9.5 mmol) were added at room temperature. After 1 hour, the reaction mixture was diluted with DCM (120 mL) and saturated NH4Cl aqueous solution (50 mL). After another 1 hour, 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 (eluted with 50% ethyl acetate / hexane) to obtain (R)-2-chloro-6 a,7,9,10-tetrahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate di-tert-butyl (3.9 g, yield 96%). LCMS C 19 H 29 ClN5O4[M+H] + Calculated m / z value: 426.2; measured value: 426.3.

[0528] Step 5: Synthesis of (R)-2-(2-hydroxyphenyl)-6a,7,9,10-tetrahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate di-tert-butyl.

[0529] [ka] 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)-dicarboxylate di-tert-butyl and 2-hydroxyphenylboronic acid (1.9 g, 14.1 mmol) is prepared in 1,4-dioxane (110 mL) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.58 g, 0.70) dichloromethane is added. mmol) was added at room temperature. The mixture was stirred at 105°C for 18 hours. The reaction product was concentrated, and the residue was purified by flash chromatography (SiO2, 200-300 mesh, siRNA / hexane = 2 / 1) to obtain (R)-2-(2-hydroxyphenyl)-6a,7,9,10-tetrahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-5,8(6H)-dicarboxylate di-tert-butyl (2.6 g, 5.4 mmol, yield 76%) as a white solid. LCMS C 25 H 34 N5O5[M+H] + Calculated m / z value: 484.3; measured value: 484.3.

[0530] Step 6: Synthesis of (R)-2-(6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol. 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)-dicarboxylate di-tert-butyl (1.3 g, 2.7 mmol) in DCM (10 mL), 2,2,2-trifluoroacetic acid (4.1 mL) was added at room temperature. After 1 hour, 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 minutes. The aqueous layer was separated and extracted with MeOH / DCM (1 / 6, 80 mL x 4). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain 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, yield 92%) as a beige solid. LCMS C 15 H 18 N5O[M+H] + Calculated m / z value: 284.2; measured value: 284.1. 1 H NMR(400 MHz,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),3.4 0-3.44(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).

[0531] 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

[0532] [ka] The title compound was prepared using appropriate starting materials and a procedure similar to that described for intermediate 9. LCMS C 15H 18 N5O[M+H] + Calculated m / z value: 284.2; measured value: 284.2.

[0533] Intermediate 12. (3R,5S)-1-((R)-2-(3-(2-bromoethoxy)isoxazole-5-yl)-3-methylbutanoyl)-5-(((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-yl acetate

[0534] [ka]

[0535] Step 1: (2S,4R)-1-((R)-2-(3-(2-bromoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0536] [ka] To a solution of (2S,4R)-1-((R)-2-(3-(2-bromoethoxy)isoxazole-5-yl)-3-methylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (intermediate 4) (100 mg, 0.14 mmol) in THF (5 mL), TBAF (0.1 mL, 7.3 mmol) in THF was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EA (20 mL), washed with brine (30 mL x 2), and the organic layer was concentrated to obtain the crude product, which was used in the next step without further purification. LCMS C 27 H 34 BrN4O5S[M+H] + Calculated m / z value: 605.1; measured value: 605.1.

[0537] Step 2: (3R,5S)-1-((R)-2-(3-(2-bromoethoxy)isoxazole-5-yl)-3-methylbutanoyl)-5-(((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-yl acetate To a solution of (2S,4R)-1-((R)-2-(3-(2-bromoethoxy)isoxazole-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (45 mg, 0.07 mmol) in DCM (5 mL), DMAP (48.0 mg, 0.37 mmol) and acetic anhydride (37.9 mg, 0.37 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with  (20 mL), and the organic layer was washed with water (2 × 10 mL), followed by saturated brine (1 × 10 mL). The organic layer was separated, dried over MgSO4, and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (PE:EA=1:1) to obtain (3R,5S)-1-((R)-2-(3-(2-bromoethoxy)isoxazole-5-yl)-3-methylbutanoyl)-5-(((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-yl acetate (40 mg, 0.06 mmol, yield 83%). LCMS C 29 H 36 BrN4O6S[M+H] + Calculated m / z value: 647.1; Measured value: 647.1

[0538] Intermediate 13. (3R,5S)-1-((R)-2-(3-(2-bromoethoxy)isoxazole-5-yl)-3-methylbutanoyl)-5-(((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-yl isobutyrate

[0539] [ka] The title compound was prepared by replacing acetic anhydride with isobutyric anhydride in step 2, using a procedure similar to that described for intermediate 12. LCMS C 31 H 40 BrN4O6S[M+H] + Calculated m / z value: 675.2; measured value: 675.2.

[0540] Intermediate 19.2-((6aS)-8-(pyrroridine-3-yl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-2-yl)phenol (diastereomer 1)

[0541] [ka]

[0542] Step 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)pyrrolidine-1-carboxylate tert-butyl (a mixture of two diastereomers).

[0543] [ka] The title compound was prepared using appropriate starting materials and a procedure similar to that described for intermediate 8, step a. LCMS C 24 H 33 N6O3[M+H] + Calculated m / z value: 453.3; measured value: 453.3.

[0544] Step 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)pyrrolidine-1-carboxylate tert-butyl (diastereomer 1)

[0545] [ka] 46.8 g of 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 tert-butyl (a mixture of two diastereomers) was purified by chiral supercritical fluid chromatography using the following conditions: Column: DAISELCHIRALPAK(registered trademark) OJ(250 * 25mm 10μm); Mobile phase: 50% EtOH / CO2; Pressure: 100 bar; Flow rate: 70 g / min; UV: 214 nM; Injection volume: 3.0 mL, 58.5 mg / mL in MeOH. 22 g of 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 tert-butyl (diastereomer 1, t r =3.0 min) was obtained. LCMS C 24 H 33 N6O3[M+H] + m / z calculated value: 453.3; measured value: 453.2. 18g of 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 tert-butyl (diastereomer 2, t r =4.5 minutes) was obtained. LCMS C 24 H 33 N6O3[M+H] + Calculated m / z value: 453.3; measured value: 453.3.

[0546] Step 3: 2-((6aS)-8-(pyrroridine-3-yl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-2-yl)phenol (diastereomer 1) To a stirred solution of 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 tert-butyl (diastereomer 1, 2.0 g, 4.4 mmol) in DCM (10 mL), TFA (1.0 mL) was added at room temperature. After 16 hours, volatile matter was removed under reduced pressure, and the residue was used in the next step without further purification. LCMS C 19 H 25 N6O[M+H] + Calculated m / z value: 353.2; measured value: 353.0.

[0547] Intermediate 20.2-((6aS)-8-(pyrroridine-3-yl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-2-yl)phenol (diastereomer 2)

[0548] [ka] To a stirred solution of 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 tert-butyl (intermediate 19, diastereomer 2 from synthesis in step 2, 2.0 g, 4.42 mmol) in DCM (10 mL), TFA (1 mL) was added at room temperature. After 16 hours, volatile matter was removed under reduced pressure, and the residue was used in the next step without further purification. LCMS C 19 H 25 N6O[M+H] + Calculated m / z value: 353.2; measured value: 353.1.

[0549] Intermediate 23. (S)-2-(8-(1-(2-(piperazine-1-yl)ethyl)piperidine-4-yl)-6,6a,7,8,9,10-Hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol

[0550] [ka]

[0551] Step 1: (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)piperidine-1-yl)ethyl)piperazine-1-carboxylate tert-butyl

[0552] [ka] To a solution of intermediate 11 (30 mg, 0.08 mmol) and 4-(2-bromoethyl)piperazine-1-carboxylate tert-butyl (40 mg, 0.14 mmol) in DMF (30 mL), NaHCO3 (13.8 mg, 0.40 mmol) was added at room temperature. The mixture was stirred at 65 °C for 48 hours. The reaction mixture was concentrated and purified by preparative TLC (MeOH:DCM = 1:10) to obtain (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)piperidine-1-yl)ethyl)piperazine-1-carboxylate tert-butyl (40 mg, 0.069 mmol, yield 84%) as a yellow solid. LCMS C 31 H 47 N8O3[M+H] + Calculated m / z value: 579.4; measured value: 579.2.

[0553] Step 2: (S)-2-(8-(1-(2-(piperazine-1-yl)ethyl)piperidine-4-yl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol To a solution of (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)piperidine-1-yl)ethyl)piperazine-1-carboxylate tert-butyl (40 mg, 0.07 mmol) in DCM (1 mL), TFA (0.03 mL, 0.16 mmol) was added at room temperature. The mixture was stirred at room temperature for 16 hours. Volatiles were removed under vacuum, and the residue was used in the next step without further purification. LCMS C 26 H 39 N8O[M+H] + Calculated m / z value: 479.3; measured value: 479.2.

[0554] Intermediate 24. (S)-2-(8-(1-(2-(piperidine-4-yl)ethyl)piperidine-4-yl)-6,6a,7,8,9,10-Hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol

[0555] [ka]

[0556] Step 1: (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)piperidine-1-yl)ethyl)piperidine-1-carbocate tert-butyl

[0557] [ka] To a solution of intermediate 11 (30.0 mg, 0.08 mmol) and 4-(2-oxoethyl)piperidine-1-carboxylate tert-butyl (27.91 mg, 0.12 mmol) in DCM (30 mL), NaBH(OAc)3 (34 mg, 0.16 mmol) was added at room temperature. The mixture was stirred at room temperature for 16 hours. Volatile substances were removed under vacuum, and the residue was purified by preparative TLC (MeOH:DCM = 1:10) to obtain (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)piperidine-1-yl)ethyl)piperidine-1-carboxylate tert-butyl (30.0 mg, 0.051 mmol, yield 63.4%) as a yellow solid. LCMS C 32 H 48 N7O3[M+H] + Calculated m / z value: 578.4; measured value: 578.1.

[0558] Step 2: (S)-2-(8-(1-(2-(piperidine-4-yl)ethyl)piperidine-4-yl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol To a solution of (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)piperidine-1-yl)ethyl)piperidine-1-carboxylate tert-butyl (40.0 mg, 0.07 mmol) in DCM (30 mL), TFA (0.3 mL) was added at room temperature. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete. Volatiles were removed under vacuum, and the residue was used in the next step without further purification. LC-MS C 27 H 40 N7O [M+H] + Calculated m / z value: 478.3; measured value: 478.2.

[0559] Intermediate 27. (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((R)-2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0560] [ka] 23 g of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide was purified by chiral supercritical fluid chromatography using the following conditions: Column: DAIEL CHIRALPAK® Whelk (250 * Mobile phase: 50% IPA / CO2; Pressure: 100 bar; Flow rate: 70 g / min; UV: 214 nM; Injection volume: 2.5 mL, 76.7 mg / mL in MeOH. 10.7g (peak 1, t r (5.0 min) (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((R)-2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide was obtained. LCMS C 31 H 45 N4O5SSi[M+H] + Calculated m / z value: 613.3; measured value: 613.3.

[0561] Intermediate 28. (S)-2-((5-((R)-1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazole-3-yl)oxy)propanoic acid

[0562] [ka]

[0563] Step 1: (S)-2-((5-((R)-1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazole-3-yl)oxy)methyl propanoate

[0564] [ka] DIAD (0.12 mL, 0.65 mmol) was added at 0°C to a stirred mixture of (2R)-2-hydroxylopanoate methyl (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-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (200 mg, 0.33 mmol), and PPh3 (171 mg, 0.65 mmol) in THF (10 mL). After 1 hour, the reaction mixture was warmed to room temperature. After a further 16 hours, volatile substances were removed under reduced pressure, and the residue was purified by preparative HPLC (eluting CH3CN in 10%-95% H2O with 0.1% NH4HCO3) to obtain (S)-2-((5-((R)-1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazole-3-yl)oxy)methyl propanoate (180 mg, 0.25 mmol, yield 77.3%) as a white solid. LCMS C 35 H 51 N4O7SSi[M+H] + Calculated m / z value: 699.3; measured value: 699.3.

[0565] Step 2: (S)-2-((5-((R)-1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazole-3-yl)oxy)propanoic acid 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-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazole-3-yl)oxy)propanoate (180 mg, 0.26 mmol) in THF (5 mL) and water (5 mL) was stirred at 0°C for 2 hours. The volatile components were removed under reduced pressure, and the residue was purified by preparative HPLC (eluting CH3CN in 10%-95% H2O with 0.1% NH4HCO3) to obtain (S)-2-((5-((R)-1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazole-3-yl)oxy)propanoic acid (150 mg, 0.21 mmol, yield 83.4%) as a white solid. LCMS C 34 H 49 N4O7SSi[M+H] + Calculated m / z value: 685.3; measured value: 685.3.

[0566] 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

[0567] [ka]

[0568] Step 1: Piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl 2-methyl

[0569] [ka] Iodomethane (2.17 g, 15.3 mmol) was added at room temperature 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). The mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was dissolved in EA (100 ml) and washed with brine (100 mL x 2). The organic layer was concentrated under vacuum to obtain piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl 2-methyl (5.2 g, 15.1 mmol, yield 99.7%) as a white solid. LCMS C 16 H 29 N2O6[M+H] + Calculated value: 345.2; Measured value: 345.2.

[0570] Step 2: 2-methylpiperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl 2-methyl

[0571] [ka] To a solution of piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl 2-methyl (5.2 g, 15.1 mmol) in THF (100 mL), LiHMDS (2.8 g, 16.6 mmol) was added at -78 °C. The mixture was stirred at -78 °C for 2 hours, and then iodomethane (6.4 g, 45.3 mmol) was added at -78 °C. The resulting mixture was stirred at room temperature for 16 hours. The reaction product was quenched at 0 °C with saturated NH4Cl aqueous solution (100 ml), diluted with EA (200 ml), and washed with water (2 × 100 mL), and then with brine (50 ml). The organic layer was dried over (MgSO4), filtered, and the filtrate was concentrated to dryness. Next, the crude product was purified by silica gel column chromatography (100-200 mesh size) (elution at PE:EA = 3:1-1:1) to obtain 2-methylpiperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl 2-methyl (5.0 g, 13.9 mmol, yield 91.4%) as a yellow oily substance. LCMS C 17 H 31 N2O6[M+H] + Calculated value: 359.2; Measured value: 359.3.

[0572] Step 3: 1,4-Bis(tert-butoxycarbonyl)-2-methylpiperazine-2-carboxylic acid

[0573] [ka] To a solution of 1,4-di-tert-butyl 2-methyl 2-methylpiperazine-1,2,4-tricarboxylic acid (5.0 g, 13.9 mmol) in THF (12 mL) / methanol (2 mL) / water (2 mL), LiOH (713 mg, 17.0 mmol) was added. The mixture was stirred at 50 °C for 16 hours. TLC indicated that the reaction was complete. The reaction mixture was washed with PE (100 mL x 2). The pH of the aqueous layer was adjusted to 3-4 with 1N HCl, and then extracted with EA (100 mL x 3). The organic layers were combined, washed with brine (50 mL), and concentrated under reduced pressure to obtain the product 1,4-bis(tert-butoxycarbonyl)-2-methylpiperazine-2-carboxylic acid (4.5 g, 13.1 mmol, yield 93.7%) as a white solid. LCMS C 16 H 29 N2O6[M+H] + Calculated value: 345.2; Measured value: 345.2.

[0574] Step 4: 2-Chloro-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate tert-butyl.

[0575] [ka] To a solution of 1,4-bis(tert-butoxycarbonyl)-2-methylpiperazine-2-carboxylic acid (4.2 g, 12.2 mmol) in DCM (25 mL), DMF (1 mL) and oxalyl chloride (4.6 g, 36.6 mmol) were added. The mixture was stirred at room temperature for 30 minutes. Volatile substances 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 hours. The reaction mixture was diluted with EA (100 mL) and washed with brine (30 mL x 2). The organic layer was concentrated under vacuum and purified by preparative TLC (extraction with PE:EA = 1:1) to obtain 2-chloro-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate tert-butyl (1.5 g, 4.2 mmol, yield 34.7%) as a yellow solid. LCMS C 15 H 21 ClN5O3[M+H] + Calculated value: 354.1; Measured value: 354.1. Step 5: 2-Chloro-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate tert-butyl

[0576] [ka]

[0577] To a solution of 2-chloro-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate tert-butyl (87.3 mg, 0.25 mmol) in THF (8 mL), BH3 (1 M, 0.74 mL, 0.74 mmol) in THF was added. The resulting mixture was stirred at 80°C for 16 hours. The reaction product was diluted with MeOH (20 ml) and stirred at 80°C for a further 16 hours. Volatiles were removed under reduced pressure, and the residue was purified by preparative TLC (DCM:MeOH = 10:1) to obtain 2-chloro-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate tert-butyl (40.0 mg, 0.12 mmol, yield 47.7%) as a yellow solid. LCMS C 15 H 23 ClN5O2[M+H] + Calculated value: 340.2; Measured value: 340.1

[0578] Step 6: 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 tert-butyl

[0579] [ka] Pd(dppf)2Cl2 (216 mg, 0.26 mmol) was added to a solution of 2-hydroxyphenylboronic acid (731 mg, 5.3 mmol), potassium carbonate (1.1 g, 7.95 mmol), and 2-chloro-6a-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylate tert-butyl (900 mg, 2.65 mmol) in 1,4-dioxane (10 mL) and water (1 mL). The mixture was stirred at 105 °C for 16 hours under N2. The reaction product was diluted with EA (200 mL) and washed with brine (100 mL x 2). The organic layer was concentrated, and the residue was purified by silica gel column chromatography (100-200 mesh size) (PE:EA = 3:1-1:1 elution) to obtain 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 tert-butyl (1.0 g, 2.51 mmol, yield 95.0%) as a yellow solid. LCMS C 21 H 28 N5O3[M+H] + Calculated value: 398.2; Measured value: 398.2.

[0580] 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 To a solution of 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 tert-butyl (60.0 mg, 0.15 mmol) in DCM (1 mL), TFA (1.2 mL) was added. The mixture was stirred at 25°C for 2 hours. The volatile components were removed under reduced pressure, and the residue was purified by preparative HPLC (eluting with CH3CN (0.1% HCl) in 5.0% to 95% H2O) to obtain 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, yield 87.9%). 1 H 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). LCMS C 16 H 20 N5O [M+H] + Calculated value: 298.2; Measured value: 298.2.

[0581] Intermediate 32: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-formylisoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0582] [ka]

[0583] Step 1: 2-(benzyloxy)acetaldehyde

[0584] [ka] To a solution of 2-(benzyloxy)ethane-1-ol (1.0 g, 6.6 mmol) in MeCN (30 mL), IBX (8.4 g, 19.7 mmol) was added. The mixture was stirred at 90°C for 10 minutes. The reaction product was diluted with toluene (30 mL) and washed with water (2 × 10 mL), then with 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 obtain 2-(benzyloxy)acetaldehyde (150 mg, 1.00 mmol). LCMS C9H 11 O2[M+H] + Calculated value: 151.1; Measured value: 151.1.

[0585] Step 2: (E)-2-(benzyloxy)acetaldehyde oxime

[0586] [ka] 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), NaOH (666 mg, 16.6 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The resulting mixture was acidified to pH 2 with HCl (5 N). The mixture was extracted with EA (30 mL x 2). The combined organic layer was washed with brine (8.0 mL), dried over MgSO4, and concentrated to obtain (E)-2-(benzyloxy)acetaldehyde oxime (500 mg, 3.0 mmol, yield 44.5%) as a colorless oil. LCMS C9H 12 NO2 [M+H] + Calculated value: 166.1; Measured value: 166.1.

[0587] Step 3: (Z)-2-(benzyloxy)-N-hydroxyacetimidoyl chloride

[0588] [ka] To a solution of (E)-2-(benzyloxy)acetaldehyde oxime (500 mg, 3.0 mmol) in DMF (10 mL), NCS (808 mg, 6.0 mmol) was added. The reaction mixture was stirred at 90°C for 2 hours. 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 obtain (Z)-2-(benzyloxy)-N-hydroxyacetimidoyl chloride (603 mg, 2.96 mmol, yield 97.8%) as a colorless oil. 1 H-NMR (CD3OD-d4,400 MHz): δ12.080(s,1H),7.324-7.369(m,5H),4.492(s,2H),4.262(s,2H).

[0589] Step 4: 2-(3-((benzyloxy)methyl)isoxazole-5-yl)ethane-1-ol

[0590] [ka] 3-Butyn-1-ol (2.76 g, 39.4 mmol) was added 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). The reaction mixture was stirred at 25°C for 2 hours. 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 obtain 2-(3-((benzyloxy)methyl)isoxazole-5-yl)ethane-1-ol (2.7 g, 11.6 mmol, yield 36.1%) as an oil. LCMS C 13 H 16 NO3 [M+H] + Calculated value: 234.1; Measured value: 234.0.

[0591] Step 5: 2-(3-((benzyloxy)methyl)isoxazole-5-yl)acetic acid

[0592] [ka] To a solution of 2-(3-((benzyloxy)methyl)isoxazole-5-yl)ethane-1-ol (100 mg, 0.43 mmol) in water (0.20 mL) and acetone (2 mL), chromium(III) oxide (65.2 mg, 0.43 mmol) and sulfuric acid (0.04 mL, 0.43 mmol) were added. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with EA (2 × 30 mL). The combined organic layer was concentrated to obtain 2-(3-((benzyloxy)methyl)isoxazole-5-yl)acetic acid (100 mg, 0.40 mmol, yield 92.5%) 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).

[0593] Step 6: 2-(3-((benzyloxy)methyl)isoxazole-5-yl)ethyl acetate

[0594] [ka] To a solution of 2-(3-((benzyloxy)methyl)isoxazole-5-yl)acetic acid (80.0 mg, 0.32 mmol) in ethanol (5 mL), sulfuric acid (0.1 mL, 0.32 mmol) was added. The reaction mixture was stirred at 70°C for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with EA (2 × 30 mL). The combined organic layer was concentrated to obtain 2-(3-((benzyloxy)methyl)isoxazole-5-yl)ethyl acetate (60 mg, 0.21 mmol, yield 66.0%) as a colorless oil. LCMS C 15 H 18 NO4 [M+H] +Calculated value: 276.1; Measured value: 276.1.

[0595] Step 7: 2-(3-((benzyloxy)methyl)isoxazole-5-yl)-3-methylbutanoate ethyl

[0596] [ka] To a solution of 2-[3-(phenylmethoxymethyl)-1,2-oxazole-5-yl]ethyl acetate (1.0 g, 3.63 mmol) and potassium tert-butoxide (815 mg, 7.26 mmol) in THF (15 mL), 2-iodopropane (926 mg, 5.45 mmol) was added at 0°C. The resulting solution was stirred at room temperature for 3 hours. 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 obtain 2-(3-((benzyloxy)methyl)isoxazole-5-yl)-3-methylbutanoate ethyl (800 mg, 2.52 mmol, yield 69.4%) as an oil.

[0597] Step 8: 2-(3-(hydroxymethyl)isoxazol-5-yl)-3-methylbutanoate ethyl

[0598] [ka] To a solution of ethyl 2-(3-((benzyloxy)methyl)isoxazole-5-yl)-3-methylbutanoate (100 mg, 0.32 mmol) in DCM (5 mL), phosphorus tribromide (0.05 mL, 0.52 mmol) was added at -78°C. The reaction mixture was stirred at room temperature for 2 hours. 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 obtain ethyl 2-(3-(hydroxymethyl)isoxazole-5-yl)-3-methylbutanoate (50 mg, 0.22 mmol, yield 69.8%) as a colorless oil. 1 H-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).

[0599] Step 9: 2-(3-(hydroxymethyl)isoxazol-5-yl)-3-methylbutanoic acid

[0600] [ka] To a solution of ethylethyl 2-(3-(hydroxymethyl)isoxazole-5-yl)-3-methylbutanoate (370 mg, 1.63 mmol) in ethanol (5 mL), NaOH (651 mg, 16.3 mmol) was added at 25 °C. The resulting solution was stirred at room temperature for 2 hours. 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 obtain 2-(3-(hydroxymethyl)isoxazole-5-yl)-3-methylbutanoic acid (320 mg, 1.6 mmol, yield 98.7%) as a colorless oil. 1H-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).

[0601] Step 10: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-(hydroxymethyl)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0602] [ka] To a solution of 2-(3-(hydroxymethyl)isoxazole-5-yl)-3-methylbutanoic acid (300.0 mg, 1.51 mmol) in DMF (2 mL), (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(4-(4-methylthiazole-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) were added. The mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with H2O and extracted with EA (20 mL x 3). The organic layers were combined and volatile matter was removed under reduced pressure. The residue was purified by silica gel chromatography to obtain (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-(hydroxymethyl)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (550 mg, 0.88 mmol, yield 58.3%) as a yellow oily substance. LCMS C 32 H 47 N4O5SSi[M+H] + Calculated value: 627.3; Measured value: 627.4.

[0603] Step 11: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-formylisoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-(hydroxymethyl)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (60 mg, 0.10 mmol) in DCM (2 mL), MnO2 (167 mg, 1.91 mmol) was added. The mixture was stirred at 45°C for 1 hour. The reaction mixture was diluted with H2O and extracted with EA (10 mL x 3). The organic layers were combined and volatile matter was removed under reduced pressure. The residue was purified by silica gel chromatography to obtain (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-formylisoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (40 mg, 0.06 mmol, yield 66.9%) as a yellow oily substance. LCMS C 32 H 45 N4O5SSi[M+H] + Calculated value: 625.3; Measured value: 625.2.

[0604] Intermediate 33: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(3-methyl-2-(3-(3-oxopropyl)isoxazole-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0605] [ka]

[0606] Steps 1-10: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-(3-hydroxypropyl)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0607] [ka]

[0608] The title compound was prepared using appropriate starting materials and a procedure similar to that described for intermediate 32 and steps 1-10. LCMS C 34 H 51 N4O5SSi[M+H] + Calculated m / z value: 655.3; measured value: 655.3.

[0609] Step 11: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(3-methyl-2-(3-(3-oxopropyl)isoxazole-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide IBX (104 mg, 0.24 mmol) was added to a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-(3-hydroxypropyl)isoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (80 mg, 0.12 mmol) in MeCN (5 mL). The mixture was stirred at 80°C for 2 hours. The reaction mixture was filtered and concentrated under vacuum to obtain (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(3-methyl-2-(3-(3-oxopropyl)isoxazole-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (80 mg, 0.12 mmol, yield 100%) as a yellow oil. LCMS C34 H 49 N4O5SSi[M+H] + Calculated m / z value: 653.3; measured value: 653.3.

[0610] Intermediate 34: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(3-methyl-2-(3-(2-oxoethyl)isoxazole-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0611] [ka] The title compound was prepared using appropriate starting materials and a procedure similar to that described for intermediate 33. LCMS C 33 H 47 N4O5SSi[M+H] + Calculated m / z value: 639.3; measured value: 639.3.

[0612] Intermediate 35: (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)methyl)piperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid

[0613] [ka]

[0614] Step 1: (2S,4R)-1-((R)-2-(3-(2-bromoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylate methyl

[0615] [ka] Potassium carbonate (3.4 g, 24.5 mmol) was added at room temperature to a solution of 1,2-dibromoethane (15.3 g, 81.6 mmol) and (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((R)-2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl)pyrrolidine-2-carboxylate methyl (3.5 g, 8.16 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 16 hours. 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 MgSO4, and concentrated to dryness. The residue was purified by preparative HPLC (eluting CH3CN (0.1% NH3.H2O) in 5.0% to 95% H2O) to obtain (2S,4R)-1-((R)-2-(3-(2-bromoethoxy)isoxazole-5-yl)-3-methylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylate methyl (1.0 g, 1.87 mmol, yield 22.9%). LCMS C 22 H 38 BrN2O6Si[M+H] + Calculated m / z value: 533.2; measured value: 533.3.

[0616] 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)piperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)pyrrolidine-2-carboxylate methyl

[0617] [ka] NaHCO3 (132 mg, 1.58 mmol) was added at room temperature to a solution of (S)-2-(8-(piperidine-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)isoxazole-5-yl)-3-methylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylate methyl (92.5 mg, 0.17 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 16 hours. 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 obtain (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-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)methyl)piperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)pyrrolidine-2-carboxylate methyl (18.0 mg, 0.021 mmol, yield 13.7%). LCMS C 43 H 65 N8O7Si[M+H] + Calculated m / z value: 833.5; measured value: 833.3.

[0618] 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)piperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid

[0619] [ka] LiOH (15.1 mg, 0.36 mmol) was added to a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-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)methyl)piperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)pyrrolidine-2-carboxylate methyl (30.0 mg, 0.04 mmol) in THF (2 mL) and water (2 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with EA (30 mL) and washed with water (2 × 10 mL) and brine (1 × 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 obtain the des-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)piperidine-1-yl)ethoxy)isoxazole-5-yl)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid (18.0 mg, 0.025 mmol, yield 70.9%). LCMS C 36 H 49 N8O7[M+H] + Calculated m / z value: 705.4; measured value: 705.5.

[0620] 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

[0621] [ka]

[0622] Step 1: 4-(3,6-dichloropyridazine-4-yl)-3-formylpiperazine-1-carboxylate tert-butyl

[0623] [ka] To a solution of 4-(3,6-dichloropyridazin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl (3.96 g, 10.9 mmol) in DCM (70 mL), Dess-Martin periodinane (9.25 g, 21.8 mmol) was added at 0°C. The mixture was stirred at 0°C for 1 hour. The reaction product was quenched with saturated Na2S2O3 aqueous solution (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 obtain the crude product 4-(3,6-dichloropyridazin-4-yl)-3-formylpiperazine-1-carboxylate tert-butyl (3.6 g, 9.97 mmol, yield 91.4%). LCMS C 14 H 19 Cl2N4O3[M+H] + Calculated m / z value: 361.1; measured value: 361.1.

[0624] Step 2: 4-(3,6-dichloropyridazin-4-yl)-3-(1-hydroxyethyl)piperazine-1-carboxylate tert-butyl

[0625] [ka] To a solution of 4-(3,6-dichloropyridazin-4-yl)-3-formylpiperazine-1-carboxylate tert-butyl (3.6 g, 9.97 mmol) in THF (70 mL), CH3MgBr (1 M in Et2O, 19.9 mL, 19.9 mmol) was added at 0°C. The mixture was stirred at 0°C for 2 hours. The reaction product was quenched with saturated NH4Cl aqueous solution (80 mL) and extracted with EA (80 mL x 3). The organic phases were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EA = 3:1) to obtain 4-(3,6-dichloropyridazin-4-yl)-3-(1-hydroxyethyl)piperazine-1-carboxylate tert-butyl (2.1 g, 5.6 mmol, yield 56.9%) as a yellow solid. LCMS C 15 H 23 Cl2N4O3[M+H] + Calculated m / z value: 377.1; measured value: 377.0.

[0626] Steps 3-7: 2-(6-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol The title compound was prepared using appropriate starting materials and a procedure similar to that described for intermediate 9 and steps 2-6. LCMS C 16 H 20 N5O[M+H] + Calculated m / z value: 298.2; measured value: 298.2. 1 H 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).

[0627] Intermediate 37. (2S,4R)-1-((2R)-2-(3-((1-bromopropan-2-yl)oxy)isoxazole-5-yl)-3-methylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0628] [ka] (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((R)-2-(3-hydroxyisoxazole-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazole-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) were dissolved in THF (10 mL), to which diisopropyl azodicarboxylate (297 mg, 1.47 mmol) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 16 hours. Volatile substances were removed under reduced pressure, and the residue was purified by silica gel chromatography (PE:EA=2:1) ​​to obtain (2S,4R)-1-((2R)-2-(3-((1-bromopropan-2-yl)oxy)isoxazole-5-yl)-3-methylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (300 mg, 0.41 mmol, yield 83.5%). LCMS C 34 H 50 BrN4O5SSi[M+H] + Calculated m / z value: 733.2; measured value: 733.4.

[0629] 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

[0630] [ka]

[0631] Step 1: (S)-(2-(2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)ethyl) tert-butyl carbamemate

[0632] [ka] 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), (2-bromoethyl)carbamate tert-butyl (24.1 mg, 0.11 mmol), and NaHCO3 (82.1 mg, 0.98 mmol) in DMF (3 mL) was stirred at 65°C for 16 hours. The reaction mixture was diluted with EA (40 mL) and washed with H2O (15 mL x 3) and brine (30 mL). The organic layer was separated, dried over Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 10:1) to obtain (S)-(2-(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 tert-butyl (40 mg, 0.094 mmol, yield 95.9%) as a pale yellow solid. LCMS C 22 H 31 N6O3[M+H] + Calculated m / z value: 427.2; measured value: 427.1.

[0633] Step 2: (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 To a solution of (S)-(2-(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 tert-butyl (40 mg, 0.094 mmol) in DCM (10 mL), TFA (1.0 mL) was added. The mixture was stirred at 25°C for 10 hours. Volatile substances were removed under reduced pressure to obtain 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). LCMS C 17 H 23 N6O[M+H] + Calculated m / z value: 327.2; measured value: 327.2.

[0634] Intermediate 39. (S)-1-(2-fluoro-4-(4-methylthiazole-5-yl)phenyl)ethane-1-amine

[0635] [ka]

[0636] Step 1: (S)-(1-(4-bromo-2-fluorophenyl)ethyl) tert-butyl carbamate

[0637] [ka] TEA (2.1 mL, 15.0 mmol) was added to a solution of (S)-1-(4-bromo-2-fluorophenyl)ethane-1-amine (1.0 g, 5 mmol) and di-tert-butyl dicarbonate (1.6 g, 7.5 mmol) in DCM (10 mL). The resulting mixture was stirred at 25°C for 1.5 hours. 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 obtain (S)-(1-(4-bromo-2-fluorophenyl)ethyl)carbamate tert-butyl (1.2 g, 3.8 mmol, yield 76.0%) as a colorless solid. LCMS C 13 H 18 BrFNO2[M+H] + Calculated m / z value: 318.0; measured value: 318.0.

[0638] Step 2: (S)-(1-(2-fluoro-4-(4-methylthiazole-5-yl)phenyl)ethyl) tert-butyl carbamate

[0639] [ka] Palladium acetate (5.71 mg, 0.03 mmol) was added to a solution of (S)-(1-(4-bromo-2-fluorophenyl)ethyl)carbamate tert-butyl (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 mixture was purged with nitrogen three times. The reaction mixture was heated to 90°C and stirred for 16 hours. The combined reaction mixture was diluted with ELISA (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 using PE / EA(6 / 1) to obtain (S)-(1-(2-fluoro-4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamate tert-butyl (36 mg, 0.093 mmol, yield 36.5%). LCMS C 17 H 22 FN2O2S[M+H] +Calculated m / z value: 337.1; measured value: 337.3.

[0640] Step 3: (S)-1-(2-fluoro-4-(4-methylthiazole-5-yl)phenyl)ethane-1-amine TFA (1.0 mL) was added to a solution of (S)-(1-(2-fluoro-4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamate tert-butyl (15 mg, 0.04 mmol) in DCM (5 mL). The resulting mixture was stirred at 25°C for 3 hours. Volatile substances were removed under reduced pressure to obtain (S)-1-(2-fluoro-4-(4-methylthiazole-5-yl)phenyl)ethane-1-amine (10 mg, 0.04 mmol, yield 94.9%) as an oil. LCMS C 12 H 14 FN2S[M+H] + Calculated m / z value: 237.1; measured value: 237.1.

[0641] Intermediate 40. (S)-1-(4-(2-methyl-1H-imidazole-1-yl)phenyl)ethane-1-amine

[0642] [ka]

[0643] Step 1: (S)-(1-(4-bromophenyl)ethyl) tert-butyl carbamemate

[0644] [ka] The title compound was prepared using appropriate starting materials and a procedure similar to that described for intermediate 39 and step 1. LCMS C9H 11 BrNO2[M+H-tBu] + Calculated m / z value: 244.0; measured value: 244.2.

[0645] Step 2: (S)-(1-(4-(2-methyl-1H-imidazole-1-yl)phenyl)ethyl) tert-butyl carbamate

[0646] [ka] CuI (74 mg, 0.39 mmol) was added to a solution of (S)-(1-(4-bromophenyl)ethyl)carbamate tert-butyl (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 mixture was purged with nitrogen three times. The reaction mixture was heated to 130 °C and stirred for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with EA (3 × 20 mL). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative TLC using EA / PE(2 / 1) to obtain (S)-(1-(4-(2-methyl-1H-imidazole-1-yl)phenyl)ethyl)carbamate tert-butyl (120 mg, 0.38 mmol, yield 9.7%) as a yellow oily substance. LCMS C 17 H 24 N3O2[M+H] + Calculated m / z value: 302.2; Measured value: 302.1

[0647] Step 3: (S)-1-(4-(2-methyl-1H-imidazole-1-yl)phenyl)ethane-1-amine TFA (1.0 mL) was added to a solution of (S)-(1-(4-(2-methyl-1H-imidazole-1-yl)phenyl)ethyl)carbamate tert-butyl (15 mg, 0.05 mmol) in DCM (5 mL). The resulting mixture was stirred at 25°C for 3 hours. Volatile substances were removed under reduced pressure to obtain (S)-1-(2-fluoro-4-(4-methylthiazole-5-yl)phenyl)ethane-1-amine (10 mg, 0.05 mmol, yield 99.8%) as an oil. LCMS C 12 H 16 N3[M+H] +Calculated m / z value: 202.1; measured value: 202.1.

[0648] Intermediate 41. (S)-1-(2-methoxy-4-(4-methylthiazole-5-yl)phenyl)ethane-1-amine

[0649] [ka]

[0650] Step 1: (S,E)-N-(1-(4-bromo-2-methoxyphenyl)ethylidene)-2-methylpropane-2-sulfinamide

[0651] [ka] To a solution of 1-(4-bromo-2-methoxyphenyl)ethanone (1.0 g, 4.4 mmol) in THF (10 mL), titanium ethoxide (2.0 g, 8.7 mmol) and (R)-tert-butanesulfinamide (635 mg, 5.24 mmol) were added. After purging three times with N2, the mixture was stirred at 70°C for 12 hours. 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 under vacuum, and the residue was purified by silica gel chromatography (PE:EA = 20:1 to 3:1) to obtain (S,E)-N-(1-(4-bromo-2-methoxyphenyl)ethylidene)-2-methylpropane-2-sulfinamide (400 mg, 1.2 mmol, yield 27%) as a yellow oil. LCMS C 13 H 19 BrNO2S[M+H] + Calculated m / z value: 332.0; measured value: 332.0.

[0652] Step 2: N-((S)-1-(4-bromo-2-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide

[0653] [ka] 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), the mixture was added and purged three times with L-selectlide (1 M, 8.73 mL, 8.73 mmol) at 0°C. The mixture was then stirred at 70°C for 12 hours. 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 under vacuum, and the residue was purified by silica gel chromatography (PE:EA = 20:1 to 1:1) to obtain N-((S)-1-(4-bromo-2-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (206 mg, 0.59 mmol, yield 51.2%) as a yellow oil. LCMS C 13 H 21 BrNO2S[M+H] + Calculated m / z value: 334.0; measured value: 334.1.

[0654] Step 3: N-((S)-1-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

[0655] [ka] To a solution of N-((S)-1-(4-bromo-2-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (175 mg, 0.52 mmol) and bis(pinacolato)diborone (200 mg, 0.79 mmol) in 1,4-dioxane (5 mL), Pd(dppf)Cl2 (38 mg, 0.05 mmol) and potassium acetate (154 mg, 1.57 mmol) were added. The resulting solution was stirred at 90°C for 16 hours under an N2 atmosphere. Volatile substances were removed under reduced pressure, and the residue was purified by silica gel chromatography (PE:EA = 10:1 to 1:1) to obtain N-((S)-1-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (160 mg, 0.4 mmol, yield 76.8%) as a solid. LCMS C 19 H 33 BNO4S[M+H] + Calculated m / z value: 382.2; measured value: 382.3.

[0656] Step 4: N-((S)-1-(2-Methoxy-4-(4-methylthiazole-5-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

[0657] [ka] 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-sulfinamide (100 mg, 0.26 mmol) and 5-bromo-4-methyl-1,3-thiazole (70 mg, 0.39 mmol) in 1,4-dioxane (5 mL), Pd(dppf)Cl2 (19 mg, 0.03 mmol) and potassium acetate (77 mg, 0.79 mmol) were added. The resulting solution was stirred at 90°C for 16 hours under an N2 atmosphere. Volatile substances were removed under reduced pressure, and the residue was purified by preparative TLC (DCM:MeOH = 20:1) to obtain N-((S)-1-(2-methoxy-4-(4-methylthiazole-5-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (50 mg, 0.14 mmol, yield 52%) as a solid. LCMS C 17 H 25 N2O2S2[M+H] + Calculated m / z value: 353.1; measured value: 353.3.

[0658] Step 5: (S)-1-(2-methoxy-4-(4-methylthiazole-5-yl)phenyl)ethane-1-amine A solution of N-((S)-1-(2-methoxy-4-(4-methylthiazole-5-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (100 mg, 0.28 mmol) in HCl (1 M, 1.42 mL, 1.42 mmol) in dioxane was stirred at room temperature for 2 hours. Volatile matter was removed under reduced pressure to obtain (S)-1-(2-methoxy-4-(4-methylthiazole-5-yl)phenyl)ethane-1-amine (60 mg, 0.24 mmol, yield 85%) as a yellow solid, which was used directly in the next step. LCMS C 13 H 17 N2OS[M+H] + Calculated m / z value: 249.1; measured value: 249.2.

[0659] 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-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0660] [ka]

[0661] Step 1: (R)-(1-(4-bromophenyl)-2-((tert-butoxycarbonyl)oxy)ethyl) tert-butyl carbamate

[0662] [ka] To a solution of (2S)-2-amino-2-(4-bromophenyl)ethanol (1.0 g, 4.6 mmol) in DCM (100 mL), di-tert-butyl dicarbonate (3.0 g, 13.9 mmol) and triethylamine (3.2 mL, 23.1 mmol) were added. The mixture was stirred at room temperature for 16 hours. Volatile substances were removed under reduced pressure, and the residue was purified by silica gel chromatography (PE:EA = 100:1~5:1) to obtain (R)-(1-(4-bromophenyl)-2-((tert-butoxycarbonyl)oxy)ethyl)carbamate tert-butyl (1.4 g, 3.4 mmol, yield 72.6%) as a colorless oil. LCMS C 18 H 27 BrNO5[M+H] + Calculated m / z value: 416.1; measured value: 416.1.

[0663] Step 2: (R)-(2-((tert-butoxycarbonyl)oxy)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl) tert-butyl carbamate

[0664] [ka] The title compound was prepared using appropriate starting materials and a procedure similar to that described for intermediate 39 and step 2. LCMS C 22 H 31 N2O5S[M+H] + Calculated m / z value: 435.2; measured value: 435.1.

[0665] Step 3: (R)-2-amino-2-(4-(4-methylthiazole-5-yl)phenyl)ethane-1-ol

[0666] [ka] To a solution of (R)-(2-((tert-butoxycarbonyl)oxy)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamate tert-butyl (1.0 g, 2.3 mmol) in DCM (10 mL), TFA (10 mL) was added. The mixture was stirred at room temperature for 2 hours. Volatile substances were removed under reduced pressure to obtain (R)-2-amino-2-(4-(4-methylthiazole-5-yl)phenyl)ethane-1-ol (741 mg, 2.2 mmol, yield 99%) as a brown oil. LCMS C 12 H 15 N2OS[M+H] + Calculated m / z value: 235.1; measured value: 235.2.

[0667] Step 4: (R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(4-methylthiazole-5-yl)phenyl)ethane-1-amine

[0668] [ka] To a solution of (R)-2-amino-2-(4-(4-methylthiazole-5-yl)phenyl)ethane-1-ol (850 mg, 3.63 mmol) in DCM (10 mL), imidazole (741 mg, 10.9 mmol) and tert-butyldimethylchlorosilane (820 mg, 5.44 mmol) were added. The mixture was stirred at room temperature for 16 hours. 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 obtain (R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(4-methylthiazole-5-yl)phenyl)ethane-1-amine (500 mg, 1.24 mmol, yield 34.3%) as a yellow oil. LCMS C 18 H 29 N2OSSi[M+H] + Calculated m / z value: 349.2; measured value: 349.2.

[0669] Step 5: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-((R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)-1-(2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl)pyrrolidine-2-carboxamide

[0670] [ka] To a stirred solution of (R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(4-methylthiazole-5-yl)phenyl)ethane-1-amine (360 mg, 1.03 mmol) and (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazole-5-yl)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid (639 mg, 1.55 mmol) in DMF (10 mL), HATU (141 mg, 2.07 mmol) and DIPEA (0.54 mL, 3.1 mmol) were added at room temperature. After 16 hours, 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 obtain (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-((R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)-1-(2-(3-hydroxyisoxazole-5-yl)-3-methylbutanoyl)pyrrolidine-2-carboxamide (200 mg, 0.23 mmol, yield 22.6%) as a yellow solid. LCMS C 37 H 59 N4O6SSi2[M+H] + Calculated m / z value: 743.4; measured value: 743.5.

[0671] Step 6: (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-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a stirred solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-((R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)-1-(2-(3-hydroxyisoxazole-5-yl)-3-methylbutanoyl)pyrrolidine-2-carboxamide (40.0 mg, 0....

Claims

1. Compound of formula (I), 【Chemistry 1】 or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, PTM is part of formula IA, 【Chemistry 2】 During the ceremony, R １ This is a covalent bond, or a chemical moiety that links PTM and ULM. ＊ This is the connection point to ULM, n = 0 to 3, W is replaced by -CH by choice. ２ -, -C(O)-, -S(O)-, or -S(O) ２ - and if n = 2 or 3, then only one W is -C(O)-, -S(O)-, or -S(O) ２ - It could be, R ｃ１ and R ｄ１ are independently H, D, halo, C １～３ alkyl, C １～３ haloalkyl, or C １～４ alkoxyl, R ｅ３ H, -C(O)R ｆ , or -P(O)(OR ｇ ) ２ And in the formula, R ｆ and R ｇ H and C are independent of each other. １～４ Alkyl, C １～４ Substitutive alkyl, C ３～８ Cyclecoalkyl, C ３～８ Substituting cyclucoalkyl, C ３～８ Heterocycline coalkyl, or C ３～８ It is a substituted heterocycline coalkyl, Z and Y are independent of N and CR. ｈ (In the formula, R ｈ = H (or absent), or R １ When bonded to Z, Z is C and Y is N or CR. ｈ (In the formula, R ｈ (is H) or R １ When bonded to Y, Y is C and Z is N or CR. ｈ (In the formula, R ｈ (is H), A compound, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 5- to 7-membered cycloalkyl ring, an optionally substituted 5- to 7-membered heteroaryl ring, or an optionally substituted 5- to 7-membered heterocyclic ring, ring B is condensed to ring C via Y and Z, and ULM is a small molecule E3 ubiquitin ligase binding site that binds to von Hippel-Lindau E3 ubiquitin ligase.

2. R １ The compound according to claim 1, wherein the bond is covalent.

3. R １ However, the chemical part is represented by the following formula, -(A) ｑ - During the ceremony, q is an integer between 1 and 14. Each A is independent of CR １ａ R １ｂ ,O,S,SO,SO ２ NR １ｃ SO ２ NR １ｃ , SONR １ｃ , SO (=NR １ｃ ), SO (=NR １ｃ ) NR １ｄ CONR １ｃ NR １ｃ CONR １ｄ NR １ｃ C(O)O, NR １ｃ SO ２ NR 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(=CNO) ２ ) NR １ｄ , 0 to 6 R １ａ and / or R １ｂ A 3- to 11-membered cycloalkyl group, with 0-6 R groups, optionally substituted at the base. １ａ and / or R １ｂ 3-11 member heterocyclines, 0-6 R groups, which are optionally substituted at the base. １ａ and / or R １ｂ aryl optionally substituted by a group, or 0 to 6 R １ａ and / or R １ｂ selected from the group consisting of heteroaryl optionally substituted by a group, In the formula, R １ａ , R １ｂ , R １ｃ , R １ｄ , and R １ｅ are each independently -H, D, -halo, -C １ ~C ８ alkyl, -O-C １ ~C ８ alkyl, -C １ ~C ６ haloalkyl, -S-C １ ~C ８ alkyl, -NHC １ ~C ８ alkyl, -N(C １ ~C ８ alkyl)₂, 3- to 11-membered cycloalkyl, aryl, heteroaryl, 3- to 11-membered heterocyclyl, -O-(3- to 11-membered cycloalkyl), -S-(3- to 11-membered cycloalkyl), NH-(3- to 11-membered cycloalkyl), N(3- to 11-membered cycloalkyl) ２ , N-(3- to 11-membered cycloalkyl)(C １ ~C ８ alkyl), -OH, -NH ２ , -SH, -SO ２ C １ ~C ８ alkyl, SO(NH)C １ ~C ８ alkyl, P(O)(OC １ ~C ８ alkyl)(C １ ~C ８ alkyl), -P(O)(OC １ ~C ８ alkyl) ２ , -C≡C-C １ ~C ８ alkyl, -C≡CH, -CH=CH(C １ ~C ８ alkyl), -C(C １ ~C ８ alkyl)=CH(C １ ~C ８ alkyl), -C(C １ ~C ８ alkyl)=C(C １ ~C ８ alkyl) ２ , -Si(OH) ３ , -Si(C １ ~C ８ Alkyl) ３ , -Si(OH)(C １ ~C ８ Alkyl) ２ , -C(O)C １ ~C ８ Alkyl, -CO ２ H, -CN, -CF ３ ,-CHF ２ ien-CH ２ F, -NO ２ , -SF ５ , -SO ２ NHC １ ~C ８ Alkyl, -SO ２ N(C) １ ~C ８ Alkyl) ２ , -SO(NH)NHC １ ~C ８ Alkyl, -SO(NH)N(C) １ ~C ８ Alkyl) ２ , -SONHC １ ~C ８ Alkyl, -SON(C) １ ~C ８ Alkyl) ２ , -CONHC １ ~C ８ Alkyl, -CON(C) １ ~C ８ Alkyl) ２ , -N(C １ ~C ８ Alkyl)CONH(C １ ~C ８ Alkyl), -N(C １ ~C ８ Alkyl)CON(C １ ~C ８ Alkyl) ２ , -NHCONH(C １ ~C ８ Alkyl), -NHCON(C １ ~C ８ Alkyl) ２ , -NHCONH ２ , -N(C １ ~C ８ Alkyl)SO ２ NH(C) １ ~C ８ Alkyl), -N(C １ ~C ８ Alkyl)SO ２ N(C) １ ~C ８ Alkyl) ２ , - NHSO ２ NH(C) １ ~C ８ Alkyl), -NHSO ２ N(C) １ ~C ８ Alkyl) ２ , or -NHSO ２ NH ２ And R １ａ or R １ｂ Each of these can be independently connected to other elements of any choice, resulting in 0 to 4 R elements. １ｅ The compound according to claim 1, which can form a cycloalkyl and / or heterocyclyl moiety that is optionally substituted with a group.

4. q = 4, R １ However, formula: -A １ -A ２ -A ３ -A ４ This is the chemical part represented by -, in the formula, A １－４ Each of these is independently O, S, SO, SO ２ NR １ｃ SO ２ NR １ｃ , SONR １ｃ , SO (=NR １ｃ ), SO (=NR １ｃ ) NR １ｄ CONR １ｃ NR １ｃ CONR １ｄ NR １ｃ C(O)O, NR １ｃ SO ２ NR 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 , selected from the group consisting of 3- to 11-membered cyclucoalkyls, 3- to 11-membered heterocyclines, aryls, and heteroaryls that are optionally substituted, In the formula, R １ａ and R １ｂ These are independently -H, D, -HALO, and -C. １ ~C ８ Alkyl, -O-C １ ~C ８ Alkyl, -C １ ~C ６ Haloalkyl, -S-C １ ~C ８ Alkyl, -NHC １ ~C ８ Alkyl, -N(C) １ ~C ８ Alkyl) 2, 3-11 member cycloalkyl, aryl, heteroaryl, 3-11 member heterocyclyl, -O- (3-11 member cycloalkyl), -S- (3-11 member cycloalkyl), NH- (3-11 member cycloalkyl), N (3-11 member cycloalkyl) ２ , N-(3-11 member cycloalkyl)(C １ ~C ８ Alkyl), -OH, -NH ２ -SH, -SO ２ C １ ~C ８ Alkyl, SO(NH)C １ ~C ８ Alkyl, P(O)(OC １ ~C ８ (Alkyl) (C １ ~C ８ Alkyl), -P(O)(OC １ ~C ８ Alkyl) ２ -C≡C-C １ ~C ８ Alkyl, -C≡CH, -CH=CH(C １ ~C ８ Alkyl), -C (C １ ~C ８ Alkyl) = CH(C １ ~C ８ Alkyl), -C (C １ ~C ８ Alkyl) = C (C １ ~C ８ Alkyl) ２ -Si(OH) ３ , -Si(C １ ~C ８ Alkyl) ３ , -Si(OH)(C １ ~C ８ Alkyl) ２ , -C(O)C １ ~C ８ Alkyl, -CO ２ H, -CN, -NO ２ , -SF ５ , -SO ２ NHC １ ~C ８ Alkyl, -SO ２ N(C) １ ~C ８ Alkyl) ２ , -SO(NH)NHC １ ~C ８ Alkyl, -SO(NH)N(C) １ ~C ８ Alkyl) ２ , -SONHC １ ~C ８ Alkyl, -SON(C) １ ~C ８ Alkyl) ２ , -CONHC １ ~C ８ Alkyl, -CON(C) １ ~C ８ Alkyl) ２ , -N(C １ ~C ８ Alkyl)CONH(C １ ~C ８ Alkyl), -N(C １ ~C ８ Alkyl)CON(C １ ~C ８ Alkyl) ２ , -NHCONH(C １ ~C ８ Alkyl), -NHCON(C １ ~C ８ Alkyl) ２ , -NHCONH ２ , -N(C １ ~C ８ Alkyl)SO ２ NH(C) １ ~C ８ Alkyl), -N(C １ ~C ８ Alkyl)SO ２ N(C) １ ~C ８ Alkyl) ２ , - NHSO ２ NH(C) １ ~C ８ Alkyl), -NHSO ２ N(C) １ ~C ８ Alkyl) ２ , or -NHSO ２ NH ２ Selected from the group consisting of, R １ｃ and R １ｄ These are C, which is replaced independently by H, D, and an arbitrary choice. １～４ Alkyl, C ３～８ Cyclecoalkyl, C ３～８ The compound according to claim 3, selected from the group consisting of heterocyclic coalkyl, aryl, or heteroaryl.

5. R １ However, 0 to 6 R １ａ and / or R １ｂ A 3- to 11-membered cycloalkyl group, with 0-6 R groups, optionally substituted at the base. １ａ and / or R １ｂ A 3- to 11-membered heterocycline, -(CR) is optionally substituted in the base. １ａ R １ｂ ) １－５ ,-(CR １ａ =CR １ｂ )-,-(CR １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (CR) １ａ R １ｂ ) １－５ -A- (CR １ａ R １ｂ ) １－５ - (In the formula, A is O, S, or NR １ｃ (CR) １ａ R １ｂ ) １－５ -A- (CR １ａ R １ｂ ) １－５ -A- (wherein 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- (wherein 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- (wherein A is O, S, or NR) １ｃ (is) - (C≡C) - (CR １ａ R １ｂ ) １－５ -A- (CR １ａ R １ｂ ) １－５ - (In the formula, A is O, S, or NR １ｃ (is) - (C≡C) - (CR １ａ R １ｂ ) １－５ ,-(CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3- to 11-membered cycloalkyl)-,-(CR) １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl) -, - (0-6 R) which are optionally substituted in the base. １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CR) １ａ R １ｂ ) １－５ -, - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ -, - (CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member cycloalkyl)-A-,-(CR) １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-A-,-(CR) １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CR) １ａ R １ｂ ) １－５ ,-(CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member cycloalkyl)-A-(wherein A is O, S, or NR) １ｃ (CR) １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CR) １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (CR) １ａ R １ｂ ) １－５ -A- (0 to 6 R's) １ａ and / or R １ｂ (3- to 11-membered cycloalkyl group optionally substituted with a base) - (wherein A is O, S, or NR １ｃ (CR) １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ ,-(CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (CR) １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-A-(wherein A is O, S, or NR) １ｃ (CR) １ａ R １ｂ ) １－５ -A- (0 to 6 R's) １ａ and / or R １ｂ (3- to 11-membered heterocyclyl) - (wherein A is O, S, or NR １ｃ (CR) １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CR) １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (CR) １ａ R １ｂ ) １－５ -A- (0 to 6 R's) １ａ and / or R １ｂ (3- to 11-membered cycloalkyl group optionally substituted with a base) - (wherein A is O, S, or NR １ｃ (CR) １ａ R １ｂ ) １－５ -A- (0 to 6 R's) １ａ and / or R １ｂ (3-11 member 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- (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(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- (wherein 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- (wherein 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)-(wherein A is O, S, or NR) １ｃ (CR) １ａ R １ｂ ) １－５ -(C≡C)-(CR １ａ R １ｂ ) １－５ -A-(CO)-(wherein A is O, S, or NR) １ｃ (CR) １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CR) １ａ R １ｂ ) １－５ -A-(CO)-(wherein A is O, S, or NR) １ｃ (CR) １ａ R １ｂ ) １－５ -A-(CO)-(0-6 R's) １ａ and / or R １ｂ (3- to 11-membered cycloalkyl group optionally substituted with a base) - (wherein A is O, S, or NR １ｃ (CR) １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ -A-(CO)-(wherein A is O, S, or NR) １ｃ (CR) １ａ R １ｂ ) １－５ -A-(CO)-(0-6 R's) １ａ and / or R １ｂ (3- to 11-membered heterocyclyl) - (wherein A is O, S, or NR １ｃ (CR) １ａ R １ｂ ) １－５ -A- (0 to 6 R's) １ａ and / or R １ｂ (3- to 11-membered cycloalkyl)-A-(CO)-(wherein each A is independently O, S, or NR) １ｃ (is) - (0 to 6 R １ａ and / or R １ｂ (3-11 member cycloalkyl)-CO-(CR) １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (CR) １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ 3 to 1 are arbitrarily replaced in the base. (1-member cycloalkyl)-(CR １ａ R １ｂ ) １－５ -A-(CO)-(wherein A is O, S, or NR) １ｃ (CR) １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ -A-(CO)-(wherein A is O, S, or NR) １ｃ (is) - (0 to 6 R １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CR) １ａ R １ｂ ) １－５ - or - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５－ , - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CO)-(CR) １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (is) - (0 to 6 R １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CO)-A-(CR) １ａ R １ｂ ) １－５ - (In the formula, A is O, S, or NR １ｃ (is) -A- (0 to 6 R １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ -A- (wherein each A is independently O, S, or NR １ｃ (is) - (0 to 6 R １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (is) - (0 to 6 R １ａ and / or R １ｂ (3-11 member heterocyclyl)-(0-6 R) which are optionally substituted in the base １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (is) - (0 to 6 R １ａ and / or R １ｂ (3-11 member heterocyclyl)-A-(CR) which are optionally substituted in the base １ａ R １ｂ ) １－５ -A- (wherein each A is independently O, S, or NR １ｃ (is) - (0 to 4 R １ａ and / or R １ｂ (Heteroaryl)-A-(CR) １ａ R １ｂ ) １－５ - (In the formula, A is O, S, or NR １ｃ (is) - (0 to 6 R １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (is) - (0 to 6 R １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CO)-(CR) １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (is) - (0 to 6 R １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CO)-A-(CR １ａ R １ｂ ) １－５ - (In the formula, A is O, S, or NR １ｃ (is) - (CO) - (0 to 6 R １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CR) １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ The compound according to claim 1 or 3, which is (i.e., is).

6. The compound according to any one of claims 1 to 5, wherein the compound of formula IA is the compound of formula IA-1. 【Transformation 3】

7. The compound according to any one of claims 1 to 5, wherein the compound of formula IA is the compound of formula IA-2. 【Chemistry 4】

8. The compound of formula IA is the compound of formula IA-3, 【Transformation 5】 In the formula, m = 1 to 3, X is replaced by arbitrary choice -CH ２ - Or it is NH, or R １ When Q is bound to X, X is either -CH or N, and Q is a -CH that is optionally substituted. ２ -, replaced by arbitrary choice - (CH ２ ) ２ -, -C(O)-, and -CH which are substituted by choice. ２ C(O)-, -S(O)-, -S(O) ２ -, optionally replaced -CH ２ S(O) ２ -, or optionally replaced with -CH ２ The compound according to any one of claims 1 to 5 or 7, wherein it is S(O)-.

9. The compound of formula IA is the compound of formula IA-4, 【Transformation 6】 In the formula, m = 1 to 3, and each R ｋ These are H, D, F, and C, independently. １～３ Alkyl, C １～３ Haloalkyl, C １～４ Alkoxyl, substituted C １～３ Alkyl, substituted C １～３ Haloalkyl or substituted C １～４ A compound according to any one of claims 1 to 5, 7, or 8, wherein the compound is an alkoxyl and s = 0 to 7.

10. The compound according to claim 9, wherein the compound of formula IA-4 is the compound of formula IA-5. 【Transformation 7】

11. The compound according to any one of claims 8 to 10, wherein m = 2.

12. At least one W is replaced by arbitrary choice - CH ２ - and if n = 2 or 3, then only one W is -C(O)-, -S(O)-, or -S(O) ２ A compound according to any one of claims 8 to 11, which may be -.

13. W is -CH ２ - The compound according to any one of claims 10 to 12.

14. W is -CH(CH ３ The compound according to any one of claims 10 to 12, wherein the compound is:

15. The compound according to any one of claims 8 to 11, wherein at least one W is -C(O)-.

16. The compound according to claim 11, wherein the compound of formula IA-5 is the compound of formula IA-6. 【Transformation 8】

17. R ｅ３ The compound according to any one of claims 1 to 16, wherein H is present.

18. R ｄ１ The compound according to any one of claims 1 to 17, wherein H is present.

19. The compound according to any one of claims 9 to 18, wherein s = 0.

20. R ｃ１ The compound according to any one of claims 1 to 15, wherein H is present.

21. ULM is the part having formula ULM-I, 【Chemistry 9】 During the ceremony, The dashed line (----) represents the R in ULM-I. １ This indicates the binding position to the V is either H or F, R ３ This is a optionally substituted phenyl, optionally substituted naphthyl, or optionally substituted 5-10 member heteroaryl. R ４ Or R ５ One of these is H, D, haloalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, -COR ｄ CONR ｅ１ R ｅ２ And, R ４ Or R ５ The other of these is either H or D, or R ４ and R ５ These, together with the carbon atom to which they are bonded, form optionally substituted 3- to 5-membered cycloalkyl or heterocycline molecules. W ３ is either an aryl that has been optionally substituted, an aryl that has been optionally substituted, or 【Chemistry 10】 R ６ and R ７ Independently, are H, D, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted haloalkyl. or R ６ , R ７ , and the carbon atoms to which they are bonded form optionally substituted cycloalkyl or optionally substituted heterocyclines, R ８ This includes heterocyclines that have been optionally substituted, heteroaryls that have been optionally substituted, aryls that have been optionally substituted, and CONR ａ R ｂ NR ａ R ｂ , 【Chemistry 11】 And, R ａ is selected from H or optionally substituted alkyl groups, R ｂ H, -C(O)- ＊ Selected from, in the formula, ＊ R １ The bond site is an 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. Each R ｃ These are independently H, halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, or haloalkoxy. Each R ｄ These are independently H, optionally substituted alkyl, or NR ｅ１ R ｅ２ Selected from, Each R ｅ１ and R ｅ２ Is it an alkyl group that is independently substituted with H, D, or any other element? or R ｅ１ and R ｅ２ These, together with the carbon atom to which they are bonded, form a 4- to 7-membered heterocycline. The compound according to any one of claims 1 to 20, wherein p is 0, 1, 2, 3, or 4.

22. R ８ The compound according to claim 21, wherein the heterocyclyl is optionally substituted.

23. R ８ The compound according to claim 21, wherein the heteroaryl is optionally substituted.

24. R ８ The compound according to claim 21, wherein the aryl is optionally substituted.

25. R ８ However, CONR ａ R ｂ The compound according to claim 21.

26. R ８ However, NR ａ R ｂ The compound according to claim 21.

27. R ８ but, 【Chemistry 12】 The compound according to claim 21.

28. R ８ but, 【Chemistry 13】 The compound according to claim 21.

29. R ８ but, 【Chemistry 14】 The compound according to claim 21.

30. R ８ but, 【Chemistry 15】 The compound according to claim 21.

31. R ８ but, 【Chemistry 16】 The compound according to claim 21.

32. R ８ but, 【Chemistry 17】 The compound according to claim 21.

33. R ８ but, [Chemistry 18] The compound according to claim 21.

34. R ８ but, 【Chemistry 19】 The compound according to claim 21.

35. R ８ but, 【Chemistry 20】 The compound according to claim 21.

36. R ３ However, it is a phenyl compound that is optionally substituted with the following formula: 【Chemistry 21】 During the ceremony, R ９ These are H, D, halo, -CN, -OH, -NO ２ , -NR ｅ１ R ｅ２ , -OR ｅ１ , -CONR ｅ１ R ｅ２ , -NR ｅ１ COR ｅ２ , -SO ２ NR ｅ１ R ｅ２ , -NR ｅ１ SO ２ R ｅ２ , optionally substituted alkyl, optionally substituted alkoxyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl, R １０ This includes H, D, halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, -NH (optionally substituted alkyl), and -N (optionally substituted alkyl). ２ , an alkoxy that is optionally substituted, or a haloalkoxy that is optionally substituted, The compound according to any one of claims 21 to 35, wherein z is 0, 1, 2, 3, or 4.

37. R ９ However, -CN, or 【Chemistry 22】 The compound according to claim 36, wherein each is optionally substituted.

38. R ９ but, 【Chemistry 23】 The compound according to claim 37.

39. R １０ However, H, D, hydroxy, halogen, -NH(C １ ~C ４ Alkyl), or C １ ~C ６ The compound according to any one of claims 36 to 38, wherein it is an alkoxy and z is 0, 1, 2, 3, or 4.

40. W ３ but, 【Chemistry 24】 And, R ６ However, it is H, R ７ However, it is an alkyl group that is substituted with H or optionally substituted, R ８ but, 【Chemistry 25】 And, R ａ However, it is an alkyl group that is substituted with H or optionally substituted, R ｂ However, H, -C(O)- ＊ And, ＊ R １ The compound according to any one of claims 21, 26, or 36-39, wherein the bond site is an optionally substituted alkyl, an optionally substituted alkylcarbonyl, or an optionally substituted (cycloalkyl)carbonyl.

41. R ７ However, H, C １～ C ６ Alkyl, C １～ C ６ alk-OH, C １～ C ６ alk-NH ２ , -C １～ C ６ alk-CONH- ＊ , or -C １～ C ６ alk-NHCO- ＊ And, R ８ However, -NH- ＊ , or -NHCOR １１ And, ＊ However, ULM's R １ It is a connection point to, R １１ but, 【Chemistry 26】 The compound according to claim 21.

42. W ３ but, 【Chemistry 27】 And, R ６ However, it is H, R ７ However, it is an alkyl group that is substituted with H or optionally substituted, R ８ but, 【Chemistry 28】 And, R ｃ The compound according to claim 21, wherein the alkyl group is H or optionally substituted, and p = 1.

43. ULM-I is a compound with the following formula: 【Chemistry 29】 ＊ However, ULM's R １ A compound according to any one of claims 21 to 42, which is a bonding site to a compound.

44. R ９ However, it is replaced with -CN or an optional character. 【Transformation 30】 And, R １０ However, H, D, hydroxy, halogen, -NH(C １ ~C ６ Alkyl), or -OC １ ~C ６ The compound according to claim 43, wherein it is alkyl.

45. R ９ but, 【Chemistry 31】 And, R １０ However, H, -F, or -OCH ３ The compound according to claim 44.

46. The compound according to any one of claims 43 to 45, wherein the compound of formula I is a compound of formula IA-7 or IA-8. 【Chemistry 32】

47. The compound of formula I is a compound of formula IA-9a or IA-10a, 【Transformation 33】 The compound according to any one of claims 43 to 46, wherein X is N or CH.

48. The compound of formula I is a compound of formula IA-11 or IA-12. 【Transformation 34】 In the formula, W is -CH ２ - or -CH(CH ３ ) - and X is either N or CH, Each R ｋ Independently, C １～３ It is an alkyl group, and s = 0 or 1. R １ is covalent bond, - 0 to 6 R's １ａ and / or R １ｂ A 3- to 11-membered cycloalkyl group that is optionally substituted at the base. 0 to 6 R's １ａ and / or R １ｂ A 3- to 11-member heterocycline that is optionally substituted in the base, -(CR １ａ R １ｂ ) １－５ 、 -(CR １ａ =CR １ｂ )-、 - (CR １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (It is) - (CR １ａ R １ｂ ) １－５ -A- (CR １ａ R １ｂ ) １－５ - (In the formula, A is O, S, or NR １ｃ (It is) - (CR １ａ R １ｂ ) １－５ -A- (CR １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (It is) -(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- (wherein A is O, S, or NR) １ｃ (It is) -(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- (wherein A is O, S, or NR) １ｃ (It is) -(C≡C)-(CR １ａ R １ｂ ) １－５ -A- (CR １ａ R １ｂ ) １－５ - (In the formula, A is O, S, or NR １ｃ (It is) -(C≡C)-(CR １ａ R １ｂ ) １－５ 、 -(CR １ａ R １ｂ ) １－５ -(3- to 11-membered cycloalkyl optionally substituted with 0 to 6 R １ａ and / or R １ｂ groups)-, - (CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl) which is optionally substituted in the base. - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CR) １ａ R １ｂ ) １－５ - - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CR) １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (It is) - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (It is) - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ - - (CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member cycloalkyl)-A-(wherein A is O, S, or NR) １ｃ (It is) - (CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-A-(wherein A is O, S, or NR) １ｃ (It is) - (CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CR) １ａ R １ｂ ) １－５ , - (CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CR) １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (It is) - (CR １ａ R １ｂ ) １－５ -A- (0 to 6 R's) １ａ and / or R １ｂ (3- to 11-membered cycloalkyl group optionally substituted with a base) - (wherein A is O, S, or NR １ｃ (It is) - (CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ , - (CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (It is) - (CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-A-(wherein A is O, S, or NR) １ｃ (It is) - (CR １ａ R １ｂ ) １－５ -A- (0 to 6 R's) １ａ and / or R １ｂ (3- to 11-membered heterocyclyl) - (wherein A is O, S, or NR １ｃ (It is) - (CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CR) １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (It is) - (CR １ａ R １ｂ ) １－５ -A- (0 to 6 R's) １ａ and / or R １ｂ (3- to 11-membered cycloalkyl group optionally substituted with a base) - (wherein A is O, S, or NR １ｃ (It is) - (CR １ａ R １ｂ ) １－５ -A- (0 to 6 R's) １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CR) １ａ R １ｂ ) １－５ -A- (wherein each A is independently O, S, or NR １ｃ (It is) - (CR １ａ R １ｂ ) １－５ -A- (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ -A- (wherein each A is independently O, S, or NR １ｃ (It is) - (CR １ａ R １ｂ ) １－５ -A- (CR １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (It is) - (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 (It is) - (CR １ａ R １ｂ ) １－５ -A-(CO)(wherein A is O, S, or NR) １ｃ (It is) - (CR １ａ R １ｂ ) １－５ - (CR １ａ =CR １ｂ ) - (CR １ａ R １ｂ ) １－５ -A-(CO)-(wherein A is O, S, or NR) １ｃ (It is) - (CR １ａ R １ｂ ) １－５ -(C≡C)-(CR １ａ R １ｂ ) １－５ -A-(CO)-(wherein A is O, S, or NR) １ｃ (It is) - (CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CR) １ａ R １ｂ ) １－５ -A-(CO)-(wherein A is O, S, or NR) １ｃ (It is) - (CR １ａ R １ｂ ) １－５ -A-(CO)-(0-6 R's) １ａ and / or R １ｂ (3- to 11-membered cycloalkyl group optionally substituted with a base) - (wherein A is O, S, or NR １ｃ (It is) - (CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ -A-(CO)-(wherein A is O, S, or NR) １ｃ (It is) - (CR １ａ R １ｂ ) １－５ -A-(CO)-(0-6 R's) １ａ and / or R １ｂ (3- to 11-membered heterocyclyl) - (wherein A is O, S, or NR １ｃ (It is) - (CR １ａ R １ｂ ) １－５ -A- (0 to 6 R's) １ａ and / or R １ｂ (3- to 11-membered cycloalkyl)-A-(CO)-(wherein each A is independently O, S, or NR) １ｃ (It is) - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member cycloalkyl)-CO-(CR) １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (It is) - (CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CR) １ａ R １ｂ ) １－５ -A-(CO)-(wherein A is O, S, or NR) １ｃ (It is) - (CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ -A-(CO)-(wherein A is O, S, or NR) １ｃ (It is) - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CR) １ａ R １ｂ ) １－５ - - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ - -A- (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ -A- (wherein each A is independently O, S, or NR １ｃ (It is) - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (It is) - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(0-6 R) which are optionally substituted in the base １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (It is) - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-A-(CR) which are optionally substituted in the base １ａ R １ｂ ) １－５ -A- (wherein each A is independently O, S, or NR １ｃ (It is) - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CO)-A-(CR) １ａ R １ｂ ) １－５ - (In the formula, A is O, S, or NR １ｃ (It is) - (0 to 4 R's) １ａ and / or R １ｂ (Heteroaryl)-A-(CR) １ａ R １ｂ ) １－５ - (In the formula, A is O, S, or NR １ｃ (It is) - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CO)-(CR) １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (It is) - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CO)-A-(CR １ａ R １ｂ ) １－５ - (In the formula, A is O, S, or NR １ｃ (is), or - (CO) - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CR) １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (is) and R ４ H, -CH ３ , or -CH ２ OH, R ７ is -C(CH ３ ) ３ or -CH(CH ３ ) ２ And, R ９ is a heteroaryl compound that is substituted with -CN or optionally, preferably 【Chemistry 35】 And, R １ａ , R １ｂ , R １ｃ , and R １ｅ These are independently -H, D, -HALO, and -C. １ ~C ８ Alkyl, -C １ ~C ６ Haloalkyl, -O-C １ ~C ８ Alkyl, -S-C １ ~C ８ Alkyl, -NHC １ ~C ８ Alkyl, -N(C) １ ~C ８ Alkyl) 2, 3-11 member cycloalkyl, aryl, heteroaryl, 3-11 member heterocyclyl, -O- (3-11 member cycloalkyl), -S- (3-11 member cycloalkyl), NH- (3-11 member cycloalkyl), N (3-11 member cycloalkyl) ２ , N-(3-11 member cycloalkyl)(C １ ~C ８ Alkyl), -OH, -NH ２ -SH, -SO ２ C １ ~C ８ Alkyl, SO(NH)C １ ~C ８ Alkyl, P(O)(OC １ ~C ８ (Alkyl) (C １ ~C ８ Alkyl), -P(O)(OC １ ~C ８ Alkyl) ２ , -C≡C-C １ ~C ８ Alkyl, -C≡CH, -CH=CH(C １ ~C ８ Alkyl), -C (C １ ~C ８ Alkyl) = CH(C １ ~C ８ Alkyl), -C (C １ ~C ８ Alkyl) = C (C １ ~C ８ Alkyl) ２ -Si(OH) ３ , -Si(C １ ~C ８ Alkyl) ３ , -Si(OH)(C １ ~C ８ Alkyl) ２ , -C(O)C １ ~C ８ Alkyl, -CO ２ H, -CN, -CF ３ ,-CHF ２ ien-CH ２ F, -NO ２ , -SF ５ , -SO ２ NHC １ ~C ８ Alkyl, -SO ２ N(C) １ ~C ８ Alkyl) ２ , -SO(NH)NHC １ ~C ８ Alkyl, -SO(NH)N(C) １ ~C ８ Alkyl) ２ , -SONHC １ ~C ８ Alkyl, -SON(C) １ ~C ８ Alkyl) ２ , -CONHC １ ~C ８ Alkyl, -CON(C) １ ~C ８ Alkyl) ２ , -N(C １ ~C ８ Alkyl)CONH(C １ ~C ８ Alkyl), -N(C １ ~C ８ Alkyl)CON(C １ ~C ８ Alkyl) ２ , -NHCONH(C １ ~C ８ Alkyl), -NHCON(C １ ~C ８ Alkyl) ２ , -NHCONH ２ , -N(C １ ~C ８ Alkyl)SO ２ NH(C) １ ~C ８ Alkyl), -N(C １ ~C ８ Alkyl)SO ２ N(C) １ ~C ８ Alkyl) ２ , - NHSO ２ NH(C) １ ~C ８ Alkyl), -NHSO ２ N(C) １ ~C ８ Alkyl) ２ , or -NHSO ２ NH ２ is or R １ａ Or R １ｂ Each of these can be independently connected to other elements of any choice, resulting in 0 to 4 R elements. １ｅ The compound according to claim 47, which can form a cycloalkyl and / or heterocyclyl moiety that is optionally substituted with a group.

49. W is -CH ２ - The compound according to claim 48.

50. R ４ However, -CH ３ The compound according to claim 48 or 49.

51. R ９ but, 【Transformation 36】 The compound according to any one of claims 48 to 50.

52. R １ but, -(CR １ａ R １ｂ ) １－５ 、 - (CR １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (It is) - (CR １ａ R １ｂ ) １－５ -A- (CR １ａ R １ｂ ) １－５ - (In the formula, A is O, S, or NR １ｃ (It is) - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CO)-(CR) １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (It is) - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CO)-A-(CR) １ａ R １ｂ ) １－５ - (In the formula, A is O, S, or NR １ｃ (It is) - (CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member cycloalkyl)-A-(wherein A is O, S, or NR) １ｃ (It is) - (CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ , - (CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (It is) -A- (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ -A- (wherein each A is independently O, S, or NR １ｃ (It is) - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (It is) - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(0-6 R) which are optionally substituted in the base １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (It is) - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-A-(CR) which are optionally substituted in the base １ａ R １ｂ ) １－５ -A- (wherein each A is independently O, S, or NR １ｃ (It is) - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (It is) - (0 to 4 R's) １ａ and / or R １ｂ (Heteroaryl)-A-(CR) １ａ R １ｂ ) １－５ - (In the formula, A is O, S, or NR １ｃ (It is) - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CO)-(CR １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ (It is) - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CO)-A-(CR １ａ R １ｂ ) １－５ - (In the formula, A is O, S, or NR １ｃ (is), or - (CO) - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CR) １ａ R １ｂ ) １－５ -A- (wherein A is O, S, or NR) １ｃ The compound according to any one of claims 48 to 51, wherein the compound is as follows:

53. Each R １ａ , each R １ｂ , and each R １ｃ However, independently, H or C １ ~C ６ The compound according to any one of claims 48 to 52, wherein it is alkyl.

54. The compound of formula I is a compound of formula IA-13a, IA-13b, IA-14a, or IA-14b. 【Chemistry 37】 The compound according to any one of claims 46 to 53, wherein X is N or CH.

55. R １ However, - (3-11 member heterocyclyl) - (CR １ａ R １ｂ ) １－３ -O- and each R １ａ However, H is, and each R １ｂ However, independently, H or -C １ ~C ８ Alkyl, preferably -CH ３ The compound according to claim 54.

56. R １ However, -(3-11 member heterocyclyl)-(CO)-(CR １ａ R １ｂ ) １－３ -O- and each R １ａ However, H is, and each R １ｂ However, independently, H or -C １ ~C ８ Alkyl, preferably -CH ３ The compound according to claim 54.

57. The compound of formula I is a compound of formula IA-15a, IA-15b, IA-16a, or IA-16b. 【Chemistry 38】 In the formula, A is O, S, or NR １ｃ And, R １ａ１ is H or -C １ ~C ８ Alkyl, preferably -CH ２ CH ３ , or -CH ３ And, R １ｃ is -H, or C １ ~C ８ Alkyl, preferably -CH ３ And, A １ is a covalent bond, or -(CR １ａ R １ｂ ) １－３ The compound according to claim 54.

58. A is O, R １ａ１ However, -C １ ~C ８ Alkyl, preferably -CH ２ CH ３ or -CH ３ The compound according to claim 57.

59. A １ The compound according to claim 57 or 58, wherein the bond is covalent.

60. R １ However, -CR １ａ =CR １ｂ - The compound according to any one of claims 1 to 54.

61. R １ However, - (CR １ａ R １ｂ ) １－５ The compound according to any one of claims 1 to 54.

62. R １ However, - (CR １ａ R １ｂ ) １－５ -A-, where A is O, S, or NR １ｃ The compound according to any one of claims 1 to 54.

63. R １ However, - (CR １ａ R １ｂ ) １－５ -A- (CR １ａ R １ｂ ) １－５ - and in the formula, A is O, S, or NR １ｃ The compound according to any one of claims 1 to 54.

64. R １ However, -(C≡C)-(CR １ａ R １ｂ ) １－５ The compound according to any one of claims 1 to 54.

65. R １ However, - (CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ The compound according to any one of claims 1 to 54, wherein the base is a 3- to 11-membered cycloalkyl group that is optionally substituted.

66. R １ However, - (CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CR) １ａ R １ｂ ) １－５ The compound according to any one of claims 1 to 54.

67. R １ However, - (CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ The compound according to any one of claims 1 to 54.

68. R １ However, - (CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ The compound according to any one of claims 1 to 54, wherein the base is a 3- to 11-membered heterocycline that is optionally substituted.

69. R １ However, - (0 to 6 R １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ - The compound according to any one of claims 1 to 54.

70. R １ However, - (CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CR) １ａ R １ｂ ) １－５ -A-, where A is O, S, or NR １ｃ The compound according to any one of claims 1 to 54.

71. R １ However, - (CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ -A-, where A is O, S, or NR １ｃ The compound according to any one of claims 1 to 54.

72. R １ However, - (CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ The base is a 3- to 11-membered heterocyclyl)-A- which is optionally substituted, where A is O, S, or NR １ｃ The compound according to any one of claims 1 to 54.

73. R １ However, - (CR １ａ R １ｂ ) １－５ -A- (0 to 6 R's) １ａ and / or R １ｂ A is a 3- to 11-membered heterocycline (which is optionally substituted in the formula), where A is O, S, or NR １ｃ The compound according to any one of claims 1 to 54.

74. R １ However, - (CR １ａ R １ｂ ) １－５ -A- (0 to 6 R's) １ａ and / or R １ｂ A is a 3- to 11-membered cycloalkyl group that is optionally substituted with a group, where A is O, S, or NR １ｃ The compound according to any one of claims 1 to 54.

75. R １ However, - (CR １ａ R １ｂ ) １－５ -A- (CR １ａ R １ｂ ) １－５ -A-, where A is O, S, or NR １ｃ The compound according to any one of claims 1 to 54.

76. R １ However, - (0 to 6 R １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CO)-(CR) １ａ R １ｂ ) １－５ -A-, where A is O, S, or NR １ｃ The compound according to any one of claims 1 to 54.

77. R １ However, - (0 to 6 R １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CO)-A-(CR) １ａ R １ｂ ) １－５ - and in the formula, A is O, S, or NR １ｃ The compound according to any one of claims 1 to 54.

78. R １ However, - (CR １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ A 3- to 11-membered cycloalkyl group is optionally substituted with a group, where A is O, S, or NR １ｃ The compound according to any one of claims 1 to 54.

79. R １ However, -A- (0 to 6 R １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ -A-, where each A is independently O, S, or NR １ｃ The compound according to any one of claims 1 to 54.

80. R １ However, - (0 to 6 R １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ - (0 to 6 R's) １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ -A-, where A is O, S, or NR １ｃ The compound according to any one of claims 1 to 54.

81. R １ However, - (0 to 6 R １ａ and / or R １ｂ (3-11 member heterocyclyl)-(0-6 R) which are optionally substituted in the base １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ -A-, where A is O, S, or NR １ｃ The compound according to any one of claims 1 to 54.

82. R １ However, - (0 to 6 R １ａ and / or R １ｂ (3-11 member heterocyclyl)-A-(CR) which are optionally substituted in the base １ａ R １ｂ ) １－５ -A-, where each A is independently O, S, or NR １ｃ The compound according to any one of claims 1 to 54.

83. R １ However, - (0 to 4 R １ａ and / or R １ｂ (Heteroaryl)-A-(CR) １ａ R １ｂ ) １－５ - and in the formula, A is O, S, or NR １ｃ The compound according to any one of claims 1 to 54.

84. R １ However, - (0 to 6 R １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CO)-(CR) １ａ R １ｂ ) １－５ -A-, where A is O, S, or NR １ｃ The compound according to any one of claims 1 to 54.

85. R １ However, - (0 to 6 R １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CO)-A-(CR １ａ R １ｂ ) １－５ - and in the formula, A is O, S, or NR １ｃ The compound according to any one of claims 1 to 54.

86. R １ However, -(CO)-(0 to 6 R １ａ and / or R １ｂ (3-11 member cycloalkyl)-(CR) １ａ R １ｂ ) １－５ -A-, where A is O, S, or NR １ｃ The compound according to any one of claims 1 to 54.

87. R １ However, - (0 to 6 R １ａ and / or R １ｂ (3-11 member heterocyclyl)-(CR) １ａ R １ｂ ) １－５ -A-, where A is O, S, or NR １ｃ The compound according to any one of claims 1 to 54.

88. The compound according to any one of claims 62, 63, or 70 to 87, wherein A is O.

89. Each R １ａ However, independently, H, -F, or -CH ３ And each R １ｂ However, independently, H or -CH ３ And each R １ｃ However, independently, H or -CH ３ The compound according to any one of claims 60 to 88.

90. A pharmaceutical composition comprising a compound according to any one of claims 1 to 89 and a pharmaceutically acceptable excipient.

91. A method for treating cancer in a subject requiring cancer treatment, comprising administering to the subject a compound according to any one of claims 1 to 89.

92. The method according to claim 91, wherein the cancer has a SMARCA4 mutation.

93. The aforementioned cancers include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma; cancers of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovaries, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas, particularly Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioblastoma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, and Schwannoma. The method according to claim 91 or 92, wherein the tumor is: 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, T-series acute lymphoblastic leukemia (T-ALL), T-series lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, precursor B-cell ALL, precursor B-cell lymphoma, large B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, and Philadelphia chromosome-positive CML.

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