Compounds for targeting mutant huntingtin protein and their use

Abstract

To provide compounds that realize effective treatment of Huntington's disease (HD).SOLUTION: The invention provides a compound of formula (I), W-L-ULM, or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers, or isotopically enriched analog thereof. In the formula: W is a compound targeting mutant huntingtin protein (mHTT); L is a bond or linking moiety optionally substituted with B; ULM is an E3 ubiquitin ligase targeting moiety; and B is a moiety that crosses the blood brain barrier and / or enhances cell permeability.SELECTED DRAWING: None

Description

[Technical Field] 【0001】 Cross-reference of related applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 810,213, filed on 25 February 2019 under Section 119(e) of the U.S. Patent Act, which is incorporated in its entirety by reference. 【0002】 The present invention generally relates to compounds that simultaneously bind to both mutant huntingtin protein (mHTT) and ubiquitin E3 ligase, and to the use of these compounds as therapeutic agents in the treatment of diseases, such as neurodegenerative disorders caused by the aggregation of mHTT. [Background technology] 【0003】 Huntington's disease (HD) is a hereditary, progressive neurodegenerative disorder characterized by motor, cognitive, and mental impairments, as well as neurodegeneration and brain atrophy that begins in the striatum and cortex and spreads to other subcortical brain regions. Huntington's disease belongs to a family of neurodegenerative diseases caused by mutations in which an enlarged CAG repeat sequence results in a long elongation of polyglutamine (polyQ) in the encoded mutant protein. This family also includes dentatorubral-pallidoluysian atrophy (DRPLA), spinal-bulbar muscular atrophy (SBMA), and spinocerebellar ataxia (SCA). Apart from these polyQ repeats, the proteins involved are irrelevant, and although they are all widely expressed in the central nervous system and peripheral tissues, they contribute to the characteristic pattern of degeneration. 【0004】 In HD, neuronal loss has also been reported in numerous other brain regions, but selective neurodegeneration of gamma-aminobutyrate-releasing spiny projection neurons in the striatum is particularly prominent. In the non-affected population, the IT that encodes the HD protein huntingtin (HTT protein) 15The number of CAG repeats in the gene varies between 6 and 35. More than 36 CAG repeats define the HD allele, leading to the translation of a mutant huntingtin protein (mHTT) containing longer polyQ elongations. This mHTT protein is prone to misfolding and aggregate formation. The length of the CAG expansion is inversely correlated with the age of disease onset, with early onset characterized by expansions of more than 60 repeats. HD has a global prevalence of 5–10 per 100,000 people and is the most common hereditary neurodegenerative disorder. 【0005】 The HTT protein is a 348 kDa multi-domain protein containing a polymorphic glutamine / proline-rich domain at its amino terminus. The longer polyQ domain of mHTT appears to induce conformational changes within the protein, leading to the formation of intracellular aggregates, which in most cases appear as nuclear inclusions. However, aggregates can also form outside the nucleus. The mHTT protein is present in the nucleus, cell body, dendrites, and nerve terminals of neurons, and is also associated with several organelles, including the Golgi apparatus, endoplasmic reticulum, and mitochondria. [Overview of the Initiative] [Problems that the invention aims to solve] 【0006】 Since HD is caused by the expression of the mHTT protein, reducing mHTT expression is an important therapeutic strategy. Reducing the amount of mHTT protein in the brains affected by HD is expected to prevent cellular dysfunction and neurodegeneration, and alleviate the symptoms of the disease. There is still a need for compounds that can effectively treat HD. [Means for solving the problem] 【0007】 A heterobifunctional molecule that simultaneously binds to both mHTT and ubiquitin E3 ligase is provided herein. 【0008】 In some embodiments, the compound of formula (I) WL-ULM (I) Alternatively, a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or isotope-enriched analog thereof is provided in the present invention. (In the formula, W is a compound that targets mutant huntingtin protein (mHTT), L is a connecting portion which is either a bond or, in some cases, is replaced by B. ULM is a region that targets E3 ubiquitin ligase. B is the portion that crosses the blood-brain barrier and / or enhances cell permeability. 【0009】 Some embodiments provide pharmaceutical compositions comprising compounds as described herein, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers or isotopic enriched analogs thereof, and pharmaceutically acceptable excipients or carriers. 【0010】 Methods for inducing the degradation of mHTT are also provided herein, comprising the step of administering a therapeutically effective amount of any of the compounds described herein, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers or isotopic enriched analogs thereof, or any of the pharmaceutical compositions described herein. 【0011】 Methods for treating Huntington's disease are also provided herein, comprising the step of administering a therapeutically effective amount of any of the compounds described herein, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or isotopic enriched analogs thereof, or pharmaceutical compositions as described herein. [Brief explanation of the drawing] 【0012】 [Figure 1A]This figure shows the degradation of mHTT using compound 1 in HeLa cells transfected with various Exon1-Qn-EGFP constructs. Analysis of soluble mHTT (Figure 1A) and aggregated HTT (Figure 1B) by MSD assay. [Figure 1B] This figure shows the degradation of mHTT using compound 1 in HeLa cells transfected with various Exon1-Qn-EGFP constructs. Analysis of soluble mHTT (Figure 1A) and aggregated HTT (Figure 1B) by MSD assay. [Figure 2] This figure shows the degradation of HTT in HeLa cells transfected with Exon1-Q73-EGFP using compound 1 and compound 10. Analysis by mHTT MSD assay. Blue circles indicate compound 1, and squares indicate compound 10. n=6(3) independent experiments. Mean + / - SEM, BG = background. [Modes for carrying out the invention] 【0013】 definition The following description outlines representative embodiments of the present invention. However, it should be recognized that such descriptions are not intended to limit the scope of the invention, but rather are provided as representative embodiments. 【0014】 Where used herein, the following words, phrases, and symbols are intended to have the meanings set forth below, unless the context in which they are used indicates otherwise. 【0015】 A dash ("-") without a space between two letters or symbols is used to indicate a substituent bond point. For example, -CONH2 is bonded via a carbon atom. 【0016】 As used herein, the terms “group,” “radical,” or “fragment” refer to a functional group or molecular fragment that can be bonded to a bond or to a fragment of another molecule. 【0017】 When a range of values is given (e.g., C 1~6 alkyl), each value within the range and all ranges intermediate thereto are included. For example, "C 1~6 alkyl" includes C1, C2, C3, C4, C5, C6, C 1~6 , C 2~6 , C 3~6 , C 4~6 , C 5~6 , C 1~5 , C 2~5 , C 3~5 , C 4~5 , C 1~4 , C 2~4 , C 3~4 , C 1~3 , C 2~3 , and C 1~2 alkyl. 【0018】 When a moiety is defined as being optionally substituted, the moiety can be substituted either as itself or as part of another moiety. For example, if R x is defined as "C 1~6 alkyl or OC 1~6 alkyl, wherein C 1~6 alkyl is optionally substituted with halogen", both the C 1~6 alkyl group alone and the C 1~6 alkyl that forms part of the OC 1~6 alkyl group can be substituted with halogen. 【0019】 The term "alkyl" encompasses linear and branched regions having the indicated number of carbon atoms, typically 1 to 20 carbon atoms, e.g., 1 to 8 carbon atoms, e.g., 1 to 6 carbon atoms. For example, C1-C6 alkyls encompass both linear and branched alkyls with 1 to 6 carbon atoms. Examples of C1-C6 alkyls include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylphenyl, etc. When an alkyl residue having a specific number of carbon atoms is named, it is intended to encompass all geometric isomers having that number of carbon atoms; therefore, for example, "butyl" means including n-butyl, sec-butyl, isobutyl, and tert-butyl, and "propyl" means including n-propyl and isopropyl. "Lower alkyl" refers to alkyl groups having 1 to 6 carbon atoms. 【0020】 "Alkylene" refers to a divalent alkyl group as defined above. As used herein, alkylene refers to a group of 1 to 10 carbon atoms (i.e., C 1~10 Alkylene), 1 to 8 carbon atoms (i.e., C 1~8 Alkylene), 1 to 6 carbon atoms (i.e., C 1~6 Alkylene), or 1 to 4 carbon atoms (i.e., C 1~4 It contains alkylene. 【0021】 A "heteroalkylene" refers to an alkylene group in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced by the same or different heteroatomic groups. The term "heteroalkylene" includes unbranched or branched saturated chains having carbon and heteroatoms. For example, one, two, or three carbon atoms may be independently replaced by the same or different heteroatomic groups. Heteroatomic groups include, but are not limited to, -NH-, -O-, -S-, -S(O)-, -S(O)2-, etc. As used herein, a heteroalkylene may consist of 1 to 8 carbon atoms, or 1 to 4 carbon atoms and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. 【0022】 The term "alkoxy" refers to alkyl groups with the indicated number of carbon atoms linked via oxygen bridges, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, etc. Alkoxy groups typically have 1 to 6 carbon atoms linked via oxygen bridges. "Lower alkoxy" refers to alkoxy groups with 1 to 6 carbon atoms. "Cycloalkoxy" similarly refers to cycloalkyl groups linked via oxygen bridges. 【0023】 "Alkenyl" refers to an unsaturated branched or linear alkyl group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon double bond derived from the removal of one hydrogen molecule from the carbon atom adjacent to the corresponding alkyl. Alkenyl groups include, but are not limited to, ethenyl, propenyl (e.g., propa-1-en-1-yl, propa-2-en-1-yl), and butenyl (e.g., buta-1-en-1-yl, buta-1-en-3-yl, buta-3-en-1-yl). "Lower alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms. 【0024】 "Alkenylene" contains at least one carbon-carbon double bond and 2 to 8 carbon atoms (i.e., C 2~8 Alkenylenes), 2 to 6 carbon atoms (i.e., C 2~6 Alkenylene), or 2 to 4 carbon atoms (i.e., C 2~4 This refers to an alkylene group containing an alkenylene. 【0025】 "Heteroalkenylene" refers to a heteroalkylene group that contains at least one carbon-carbon double bond and has 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms, and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. 【0026】 The term "alkenyloxy" refers to an -O-alkenyl group, where alkenyl is defined as described herein. 【0027】 "Alkynyl" refers to an unsaturated branched or linear alkyl group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond derived from the removal of two hydrogen molecules from the adjacent carbon atoms of the corresponding alkyl. Alkynyl groups include, but are not limited to, ethynyl, propynyl (e.g., propa-1-in-1-yl, propa-2-in-1-yl), and butynyl (e.g., buta-1-in-1-yl, buta-1-in-3-yl, buta-3-in-1-yl). "Lower alkynyl" refers to an alkynyl group having 2 to 6 carbon atoms. 【0028】 "Alkynylene" contains at least one carbon-carbon triple bond and 2 to 8 carbon atoms (i.e., C 2~8 Alkynylene), 2 to 6 carbon atoms (i.e., C 2~6 Alkynylene), or 2 to 4 carbon atoms (i.e., C 2~4 This refers to an alkylene group having an alkynylene. The term "alkynyl" also includes groups having one triple bond and one double bond. 【0029】 "Heteroalkylene" refers to a heteroalkylene group that contains at least one carbon-carbon triple bond and has 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms, and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. The term "alkynyl" also includes groups having one triple bond and one double bond. 【0030】 The term "alkynyloxy" refers to the -O-alkynyl group, where alkynyl is as described herein. 【0031】 The term "aryl" refers to an aromatic carbocyclic ring having the indicated number of carbon atoms, e.g., 6 to 12 or 6 to 10 carbon atoms. Aryl groups can be monocyclic or polycyclic (e.g., dicyclic, tricyclic). In some cases, both rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other cases, a polycyclic aryl group can include a non-aromatic ring fused with an aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl), provided that the polycyclic aryl group is bonded to the parent structure via atoms in the aromatic ring. Thus, the 1,2,3,4-tetrahydronaphthalene-5-yl group (where the portion is bonded to the parent structure via aromatic carbon atoms) is considered an aryl group, while the 1,2,3,4-tetrahydronaphthalene-1-yl group (where the portion is bonded to the parent structure via non-aromatic carbon atoms) is not considered an aryl group. Similarly, the 1,2,3,4-tetrahydroquinoline-8-yl group (which is bonded to the parent structure via an aromatic carbon atom) is considered an aryl group, while the 1,2,3,4-tetrahydroquinoline-1-yl group (which is bonded to the parent structure via a non-aromatic nitrogen atom) is not considered an aryl group. However, the term "aryl" does not encompass or overlap with "heteroaryl" regardless of the bonding site (for example, both quinoline-5-yl and quinoline-2-yl are heteroaryl groups). In some cases, aryl is phenyl or naphthyl. In certain specific cases, aryl is phenyl. 【0032】 "Aralkyr" refers to "-alkylene-aryl". 【0033】 "Arylene" refers to a divalent aryl group as defined above. 【0034】 Divalent radicals formed from substituted benzene derivatives, which have free valence on the ring atom, are called substituted phenylene radicals. Divalent radicals derived from monovalent polycyclic hydrocarbon radicals whose names end in "-yl" due to the removal of one hydrogen atom from a carbon atom with free valence are named by adding "-idene" to the name of the corresponding monovalent radical. For example, a naphthyl group with two bonding sites is called naphthylidene. 【0035】 "Cycloalkyl" refers to a non-aromatic, fully saturated carbon ring having the indicated number of carbon atoms, e.g., 3 to 10, 3 to 8, or 3 to 6 ring carbon atoms. Cycloalkyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentenyl, and cyclohexyl, as well as cross-linked and caged ring groups (e.g., norbornane, bicyclo[2.2.2]octane). In addition, one ring of a polycyclic cycloalkyl group may be aromatic, provided that the polycyclic cycloalkyl group is bonded to the parent structure via a non-aromatic carbon atom. For example, the 1,2,3,4-tetrahydronaphthalene-1-yl group (the portion bonded to the parent structure via a non-aromatic carbon atom) is a cycloalkyl group, while 1,2,3,4-tetrahydronaphthalene-5-yl (the portion bonded to the parent structure via an aromatic carbon atom) is not considered a cycloalkyl group. Examples of polycyclic cycloalkyl groups consisting of a cycloalkyl group fused with an aromatic ring are listed below. 【0036】 "Cycloalkylene" refers to a divalent cycloalkyl group as defined above. 【0037】 A "cycloalkenyl" refers to a non-aromatic carbocyclic group containing the indicated number of carbon atoms (e.g., 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms) and at least one carbon-carbon double bond derived from the removal of one hydrogen molecule from an adjacent carbon atom of the corresponding cycloalkyl group. Cycloalkenyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl, as well as bridged and caged ring groups (e.g., bicyclo[2.2.2]octene). In addition, one ring of a polycyclic cycloalkenyl group may be aromatic, provided that the polycyclic alkenyl group is bonded to the parent structure via a non-aromatic carbon atom. For example, indene-1-yl (the portion is bonded to the parent structure via a non-aromatic carbon atom) is considered a cycloalkenyl group, while indene-4-yl (the portion is bonded to the parent structure via an aromatic carbon atom) is not considered a cycloalkenyl group. Examples of polycyclic cycloalkenyl groups consisting of a cycloalkenyl group fused with an aromatic ring are described below. 【0038】 The term "cycloalkoxy" refers to -O-cycloalkyl, where cycloalkyl is as defined herein. 【0039】 The term "cyano" refers to -CN. 【0040】 The term "halo" includes fluoro, chloro, bromo, and iodine, while the term "halogen" includes fluorine, chlorine, bromine, and iodine. 【0041】 "Haloalkyl" includes linear and branched carbon chains having the indicated number of carbon atoms (e.g., 1 to 6 carbon atoms) substituted with at least one halogen atom. If a haloalkyl group contains more than one halogen atom, the halogens may be the same (e.g., dichloromethyl) or different (e.g., chlorofluoromethyl). Examples of haloalkyl groups, but not limited to these, include chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 2-chloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl, 1,2-dichloroethyl, pentachloroethyl, and pentafluoroethyl. 【0042】 "Heteroaryl" represents an aromatic ring (e.g., 5-12 membered or 5-10 membered heteroaryl) containing the indicated number of atoms, composed of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms), with the remaining ring atoms being carbon. Heteroaryl groups do not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in a heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in a heteroaryl group is 1 or less. Unless otherwise specified, heteroaryl groups can be bonded to the parent structure by carbon or nitrogen atoms, if the valence allows. For example, "pyridyl" includes 2-pyridyl, 3-pyridyl, and 4-pyridyl groups, and "pyrrolyl" includes 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl groups. When nitrogen is present in a heteroaryl ring, it can exist in an oxidized state (i.e., N) if the properties of the adjacent atoms and groups allow it. + -O - ). In addition, when sulfur is present in a heteroaryl ring, if the properties of the adjacent atoms and groups allow it, sulfur can exist in an oxidized state (i.e., S + -O - (or SO2). The heteroaryl group may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). 【0043】 In some cases, the heteroaryl group is monocyclic. Examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine), and tetrazine. 【0044】 In some cases, both rings of a polycyclic heteroaryl group are aromatic. Examples include indole, isoindole, indazole, benzimidazole, benzotriazole, benzofuran, benzoxazole, benzoisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzoisothiazole, benzothiadiazole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, and 1H-pyrazolo[4,3-b] Pyridine, 1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine, 3H-imidazo[4,5-c]pyridine, 3H-[1,2,3]triazolo[4,5-c]pyridine, 1H-pyrrolo[3,2-c]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-imidazo[4,5-c]pyridine, 1H-[1,2,3]triazolo[4,5-c]pyridine, flo[2,3-b]pyridine, oxazolo[5,4- [b]pyridine, isoxazolo[5,4-b]pyridine, [1,2,3]oxadiazolo[5,4-b]pyridine, flou[3,2-b]pyridine, oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine, [1,2,3]oxadiazolo[4,5-b]pyridine, flou[2,3-c]pyridine, oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine, [1,2,3]oxadiazolo[5,4-c]pyridine, flou[3,2-c]pyridine, oxazolo[4,5-c]pyridine, isoxazolo [4,5-c]pyridine, [1,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine, thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine, [1,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pyridine, thiazolo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine, [1,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3-c]pyridine, thiazolo[5,4-c]pyridine, isothiazolo[5,4-c]pyridine, [1,2,3] Thiadhiazolo[5,4-c]pyridine, thieno[3,2-c]pyridine, thiazolo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine, [1,2,3]thiadiazolo[4,5-c]pyridine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine (e.g., 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine), imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole, 1H-pyrazolo[4,3-d]thiazole, and imidazo[2,1-b]thiazole. 【0045】 In other cases, a polycyclic heteroaryl group can include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused with a heteroaryl ring, provided that the polycyclic heteroaryl group is bonded to the parent structure via an atom in the aromatic ring. For example, the 4,5,6,7-tetrahydrobenzo[d]thiazole-2-yl group (the portion of which is bonded to the parent structure via an aromatic carbon atom) is considered a heteroaryl group, while the 4,5,6,7-tetrahydrobenzo[d]thiazole-5-yl group (the portion of which is bonded to the parent structure via a non-aromatic carbon atom) is not considered a heteroaryl group. 【0046】 "Heteroaralkyl" refers to the "-alkylene-heteroaryl" group. 【0047】 "Heteroarylene" refers to a divalent heteroaryl group as defined above. 【0048】 "Heteroaryloxy" refers to "-O-heteroaryl". 【0049】 "Hypercycloalkyl" refers to a non-aromatic, fully saturated ring (e.g., 3-10 membered or 3-7 membered heterocycloalkyl) having the indicated number of atoms, composed of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms), with the remaining ring atoms being carbon. Heterocycloalkyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). 【0050】 Examples of monocyclic heterocycloalkyl groups include oxyranil, azilidinil, azetidinil, pyrrolidinil, imidazolidinil, pyrazolidinil, piperidinil, piperazinil, morpholinil, and thiomorpholinil. 【0051】 When nitrogen is present in a heterocycloalkyl ring, if the properties of the adjacent atoms and groups allow it, nitrogen can exist in an oxidized state (i.e., N + -O - Examples include piperidinyl N-oxide and morpholinyl N-oxide. In addition, when sulfur is present in a heterocycloalkyl ring, sulfur can exist in an oxidized state (i.e., S) if the properties of the adjacent atoms and groups allow it. + -O - (or SO2-). Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide. 【0052】 In addition, provided that the polycyclic heterocycloalkyl group is bonded to the parent structure via a non-aromatic carbon or nitrogen atom, one of the rings of the polycyclic heterocycloalkyl group can be aromatic (e.g., aryl or heteroaryl). For example, the 1,2,3,4-tetrahydroquinoline-1-yl group (which is bonded to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkyl group, while the 1,2,3,4-tetrahydroquinoline-8-yl group (which is bonded to the parent structure via an aromatic carbon atom) is not considered a heterocycloalkyl group. 【0053】 "Heterocycloalkylene" refers to a divalent heterocycloalkyl group as defined above. 【0054】 "Hypercycloalkenyl" represents a non-aromatic ring (e.g., 3-10 membered or 3-7 membered heterocycloalkyl) having the indicated number of atoms, composed of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms), with the remaining ring atoms being carbon, and having at least one double bond derived from the removal of a hydrogen molecule from an adjacent carbon atom, an adjacent nitrogen atom, or an adjacent carbon and nitrogen atom of the corresponding heterocycloalkyl. The heterocycloalkenyl group can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). If nitrogen is present in the heterocycloalkenyl ring, nitrogen may exist in an oxidized state (i.e., N) if the properties of the adjacent atoms and the group allow it. + -O - ). In addition, when sulfur is present in a heterocycloalkenyl ring, if the properties of the adjacent atoms and groups allow it, sulfur can exist in an oxidized state (i.e., S + -O -(or -SO2-). Examples of heterocycloalkenyl groups include dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydrothiophenyl (e.g., 2,3-dihydrothiophenyl, 2,5-dihydrothiophenyl), dihydropyrrolyl (e.g., 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-pyrrolyl), dihydroimidazolyl (e.g., 2,3-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl), pyranyl, dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl), tetrahydropyridinyl (e.g., 1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl), and dihydropyridine (e.g., 1,2-dihydropyridine, 1,4-dihydropyridine). In addition, provided that the polycyclic heterocycloalkenyl group is bonded to the parent structure via a non-aromatic carbon or nitrogen atom, one of the rings of the polycyclic heterocycloalkenyl group can be aromatic (e.g., aryl or heteroaryl). For example, the 1,2-dihydroquinoline-1-yl group (which is bonded to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkenyl group, while the 1,2-dihydroquinoline-8-yl group (which is bonded to the parent structure via an aromatic carbon atom) is not considered a heterocycloalkenyl group. 【0055】 The terms "hydroxy" or "hydroxyl" refer to the -OH group. 【0056】 "(lower alkyl)thio" refers to the "lower alkyl-S-" group. 【0057】 "Oxo" refers to (=O) or an (O) group. 【0058】 The terms “optional” or “depending on the circumstances” mean that the events or situations described thereafter may or may not occur, and that the description includes both the cases in which the events or situations occur and the cases in which they do not. For example, “optionally substituted alkyl” includes both “alkyl” and “substituted alkyl” as defined herein. With respect to any group containing one or more substituents, it will be understood by those skilled in the art that such groups are not intended to induce any substitutions or substitution patterns that are sterically impractical, synthetically unrealistic, and / or inherently unstable. 【0059】 Where used herein, the term "substituted" means that any one or more hydrogen atoms on a specified atom or group are replaced with those selected from the indicated groups, provided that the normal valency of the specified atom is not exceeded. If the substituent is oxo (i.e., =O), then two hydrogen atoms on the atom are substituted. Combinations of substituents and / or variable elements are permitted only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure means a compound that is robust enough to survive isolation from the reaction mixture and suggests a subsequent formulation as a drug with at least practical utility. Unless otherwise specified, substituents are named within the core structure. For example, if (cycloalkyl)alkyl is included as a possible substituent, it should be understood that the bonding site of this substituent to the core structure is on the alkyl portion. 【0060】 The terms "substituted" alkyl (including C1-C4 alkyls without limitation), cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl, and heteroaryl mean that, unless otherwise clearly defined, one or more (e.g., up to 5, e.g., up to 3) hydrogen atoms are present. -R a , -OR b -O(C1~C2 alkyl)O-(e.g., methylenedioxy-), -SRb , guanidine (-NHC(=NH)NH2), guanidine in which one or more hydrogen atoms of guanidine are replaced by C1-C4 alkyl groups, -NR b R c , halo, cyano, oxo (as substituents for heterocycloalkyls), nitro, -COR b , -CO2R b ,-CONR b R c , -OCOR b , -OCO2R a ,-OCONR b R c , -NR c COR b , -NR c CO2R a , -NR c CONR b R c -SOR a , -SO2R a -SO2NR b R c , and -NR c SO2R a (In the formula, R a These are selected from C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl. R b It is selected from H, C1-C6 alkyl, aryl and heteroaryl, R c is selected from hydrogen and C1-C4 alkyl, or R b and R c , and the nitrogen atoms to which these are bonded form heterocycloalkyl groups, Each C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl may be C1-C4 alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl-, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 haloalkyl, Halo, -OH, -NH2, -C1~C4alkyl-NH2, -N(C1~C4alkyl)(C1~C4alkyl), -NH(C1~C4alkyl), -N(C1~C4alkyl)(C1~C4alkylphenyl), -N(C1~C4alkyl)(C1~C4alkylheteroaryl), -NH(C1~C4alkylphenyl), cyano, nitro, oxo (as a substituent of heteroaryl), -CO2H, -C(O)OC1~C4alkyl, -CON(C1~C4alkyl)(C -C1-C4 alkyl, -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, -C(O)C1-C4 phenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, -SO2(C1-C4 alkyl), -SO2(aryl), -SO2 (Substituted with one or more substituents, e.g., 1, 2, or 3 substituents, independently selected from (heteroaryl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(aryl), -SO2NH(heteroaryl), -SO2(aryl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl), -NHSO2(aryl), -NHSO2(heteroaryl), and -NHSO2(C1-C4 haloalkyl)) These refer to alkyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl, and heteroaryl substituents, respectively, which are replaced by substituents independently selected from the given substituents. 【0061】 The term "amino" refers to the -NH2 group. 【0062】 The term "(alkyl)amino" refers to the -NH(alkyl) group, where alkyl is as described herein. 【0063】 The term "di(alkyl)amino" refers to the -N(alkyl)(alkyl) group, where alkyl is as described herein. 【0064】 The term "substituted amino" refers to -NHR d or -NR d R d group, where each R d is independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted acyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, alkoxycarbonyl, sulfinyl and sulfonyl, and the substituted alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl have one or more (e.g., up to 5, e.g., up to 3) hydrogen atoms replaced by -R a , -OR b , -O(C1-C2 alkyl)O- (e.g., methylenedioxy-), -SR b , guanidine, guanidine in which one or more hydrogens of guanidine are replaced by lower alkyl groups, -NR b R c , halo, cyano, nitro, -COR b , -CO2R b , -CONR b R c , -OCOR b , -OCO2R a , -OCONR b R c , -NR c COR b , -NR c CO2R a , -NR c CONRb R c , -CO2R b ,-CONR b R c , -NR c COR b -SOR a , -SO2R a -SO2NR b R c and -NR c SO2R a (In the formula, R a These are selected from optionally substituted C1-C6 alkyl groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups. R b This is selected from H, optionally substituted C1-C6 alkyl groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups. R c This is selected from C1-C4 alkyl groups which are hydrogen and optionally substituted. In each case, the substituted group is either unsubstituted or C1~C4 alkyl, aryl, heteroaryl, aryl-C1~C4 alkyl-, heteroaryl-C1~C4 alkyl-, C1~C4 haloalkyl-, -OC1~C4 alkyl, -OC1~C4 alkylene-aryl, -OC1~C4 alkylene-heteroaryl, -C1~C4 alkyl-OH, -OC1~C4 haloalkyl, halo, -OH, -NH2, -C1~C4 alkyl-NH2, -N(C1~C4 alkyl)(C1~C 4 alkyl), -NH(C1~C4 alkyl), -N(C1~C4 alkyl)(C1~C4 alkylene aryl), -N(C1~C4 alkyl)(C1~C4 alkyl heteroaryl), -N(C1~C4 alkyl)(C1~C4 alkyl heteroaryl), -NH(C1~C4 alkylphenyl), cyano, nitro, oxo (as substituents for heteroaryls), -CO2H, -C(O)OC1~C4 alkyl, -CON(C1~C4 alkyl)(C1~C4 alkyl), -CONH(C1 ~C4alkyl), -CONH2, -NHC(O)(C1~C4alkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -N(C1~C4alkyl)C(O)(C1~C4alkyl), -N(C1~C4alkyl)C(O)(aryl), -N(C1~C4alkyl)C(O)(heteroaryl), -C(O)C1~C4alkyl, -C(O)C1~C6aryl, -C(O)heteroaryl, -C(O)C1~C4 haloalkyl, -OC(O)C1~C4alkyl, -SO (Independently selected from 2(C1-C4 alkyl), -SO2(aryl), -SO2(heteroaryl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(aryl), -SO2NH(heteroaryl), -NHSO2(C1-C4 alkyl), -NHSO2(aryl), -NHSO2(heteroaryl), and -NHSO2(C1-C4 haloalkyl), and independently substituted with one or more substituents, for example, 1, 2, or 3 substituents.) These refer to alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl substituents, respectively, which are independently selected from the given substituents. 【0065】 The term "substituted amino acid" is also used in -NR. e R f It refers to the base, R e and R f These, together with the nitrogen to which they are bonded, form a optionally substituted 5- to 7-membered nitrogen-containing non-aromatic heterocycle, optionally containing one or two additional heteroatoms selected from nitrogen, oxygen, and sulfur. 【0066】 "Aminocarbonyl" encompasses the group of the formula -(C=O)(optionally substituted amino), where the substituted amino is as described herein. 【0067】 "Alkylaminocarbonyl" refers to -C(=O)((alkyl)amino), where (alkyl)amino is as defined herein. 【0068】 "Di(alkyl)aminocarbonyl" refers to -C(=O)(di(alkyl)amino), where di(alkyl)amino is as defined herein. 【0069】 The compounds described herein include, but are not limited to, their optical isomers, racemates, and other mixtures thereof. In these situations, a single enantiomer or diastereomer, i.e., an optically active form, can be obtained by asymmetric synthesis or by the resolution of a racemate. Resolution of a racemate can be achieved, for example, by conventional methods such as crystallization in the presence of a resolving agent, or by chromatography using a chiral high-pressure liquid chromatography (HPLC) column. The term "isomer" refers to different compounds having the same molecular formula. The term "stereoisomer" refers to isomers that differ only in the way their atoms are arranged in space. The term "enantiomer" refers to stereoisomers that are mirror images of each other and cannot be superimposed. A 1:1 mixture of pairs of enantiomers is a "racemic" mixture. The symbol "(±)" may be used to indicate a racemic mixture as needed. The term "diastereoisomer" refers to stereoisomers that have at least two chiral atoms but are not mirror images of each other. Absolute stereochemistry is determined by the Cahn-Ingold-Prelog RS system. If a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be indicated by either R or S. For split compounds whose absolute configuration is unknown, they can be indicated by (+) or (-) depending on the direction in which they rotate plane-polarized light at the wavelength of the sodium D line (right-handed or left-handed). 【0070】 In this specification, if a compound exists in various tautomer forms, the term “compound” includes all tautomer forms of the compound. Such compounds also include crystalline forms, including polymorphs and clathrates. Similarly, the term “salt” includes all tautomer and crystalline forms of the compound. The term “tautomer” refers to structurally distinct isomers that interconvert by tautomerization. Tautomerization is a form of isomerization, including prototropic or proton-transfer tautomerization, and is considered a subset of acid-base chemistry. Prototropic or proton-transfer tautomerization involves the transfer of protons, often accompanied by a change in bond order, such as the exchange of a single bond with an adjacent double bond. When tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be achieved. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion between pentan-2,4-dione and its 4-hydroxypenta-3-en-2-one tautomer. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion between pyridine-4-ol and its pyridine-4(1H)-one tautomer. 【0071】 The pharmaceutically acceptable forms of the compounds listed herein include their pharmaceutically acceptable salts and mixtures. In some embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts. 【0072】 "Pharmacologically acceptable salts" include, but are not limited to, salts with inorganic acids such as hydrochlorates, phosphates, diphosphates, hydrobromides, sulfates, sulfinates, and nitrates; and salts with organic acids such as malates, maleates, fumarates, tartrates, succinates, citrates, acetates, lactates, methanesulfonates, p-toluenesulfonates, 2-hydroxyethylsulfonates, benzoates, salicylates, stearates, haloalkanoates such as trifluoroacetates, and alkanoates such as acetates, HOOC(CH2) where n is 0-4. nThis includes salts such as -COOH. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium. In addition, when the compounds described herein are obtained as acid addition salts, the free base can be obtained by basicizing a solution of the acid salt. Conversely, when the product is a free base, the addition salt, in particular a pharmaceutically acceptable addition salt, can be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from a main component. Those skilled in the art will recognize the various synthetic methodologies that can be used to prepare non-toxic, pharmaceutically acceptable addition salts. 【0073】 Any compound or structure shown herein is intended to represent the unlabeled form of the compound and the “isotope-enriched analog.” Compounds in isotope-enriched form may also be referred to as “labeled.” An isotope-enriched analog has the structure shown herein except that one or more atoms are enriched with an isotope having a selected atomic weight or mass number. Examples of isotopes that can be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, respectively 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125 I is included. Generally, isotope-enriched analogs include compounds that have any isotope enrichment exceeding the natural abundance of the isotope (e.g., on the Earth's surface). Various isotope-labeled compounds, e.g., radioactive isotopes, e.g. 3 H, 18 F, 11 C,13 C and 14 The present invention includes the incorporation of C. 18 F, 3 H or 11 Compounds labeled with 1C may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission tomography (SPECT) including drug or substance tissue distribution assays, or in radiation therapy for patients. 【0074】 The term “isotope-enriched analog” includes “deuterated analogs” of the compounds described herein in which one or more hydrogen atoms, for example, a hydrogen atom on a carbon atom, are replaced by deuterium. Such compounds can exhibit increased metabolic resistance and may therefore be useful for increasing the half-life of any compound when administered to mammals, particularly humans. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. Vol. 5 (No. 12): pp. 524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by utilizing starting materials in which one or more hydrogen atoms are replaced by deuterium. 【0075】 The deuterium-labeled or substituted compounds of the present invention may have improved DMPK (drug metabolism and pharmacokinetic) properties related to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may result in certain therapeutic benefits due to greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. The isotope-labeled compounds of the present invention are generally prepared by performing the procedures disclosed in the schemes or examples and preparations described below, by using readily available isotope-labeled reagents instead of unlabeled reagents. When a compound is described as a deuterated analog, the compound may be depicted with deuterium as a substituent. 【0076】 The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of this invention, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically indicated as "H" or "hydrogen," the position is understood to have hydrogen and its isotopes in their natural abundances. 【0077】 As used herein, the terms “huntingtin protein” or “HTT protein” as β-amyloid aggregates refer to the protein encoded by the human huntingtin gene (HTT gene) located at position 16.3 on the short (p) arm of chromosome 4. More precisely, the IT15 gene encoding the HTT protein is located at base pairs 3,076,407 to 3,245,686 on chromosome 4. 【0078】 As used herein, the term "β-amyloid aggregate" refers to insoluble fibrous amyloid containing misfolded β-amyloid protein molecules. 【0079】 As used herein, the term "HTT protein aggregate" refers to insoluble fibrous amyloid containing misfolded HTT protein molecules. 【0080】 The term "mutant huntingtin protein" or "mHTT protein" refers to a polyglutamine-enlarged version of the HTT protein produced by the expansion of the CAG repeat in the huntingtin gene. This variant form of the HTT protein is prone to misfolding and aggregate formation. 【0081】 The term "compounds that target mutant huntingtin protein" refers to compounds that can bind to mHTT. 【0082】 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. E3 ubiquitin ligases, either alone or in complex with E2 ubiquitin-conjugating enzymes, are involved in the transfer of ubiquitin to target proteins. Generally, ubiquitin ligases are involved in polyubiquitination (marking proteins for degradation by the proteasome), such as when a second ubiquitin binds to a first ubiquitin and a third ubiquitin binds to a second ubiquitin. 【0083】 The term "E3 ubiquitin ligase targeting moiety" refers to a molecule that can bind to and / or recruit E3 ubiquitin ligase. 【0084】 The term "VHL ligase targeting moiety" refers to a molecule that can bind to and / or recruit von Hippel-Lindau (VHL). 【0085】 The term "cerebronol ligase targeting moiety" refers to a molecule that can bind to and / or recruit cerebron (CRBN). 【0086】 The term "cell inhibitor-targeting moiety of apoptosis protein 1" refers to a molecule that can bind to and / or recruit a cell inhibitor of apoptosis protein 1 (cIAP1). 【0087】 The term “blood-brain barrier” or “BBB” refers to the physiological barrier between the peripheral circulation and the brain and spinal cord that restricts the transport of molecules into the brain. The blood-brain barrier within the brain, the blood-spinal cord barrier within the spinal cord, and the blood-retinal barrier within the retina are a continuous capillary barrier within the central nervous system and are collectively referred to herein as the blood-brain barrier or BBB. The BBB also includes the blood-CSF barrier (choroid plexus), which is composed more of ependymal cells than capillary endothelial cells. 【0088】 The term “substances that cross the blood-brain barrier and / or enhance cell permeability” refers to molecules or macromolecules that are capable of being transported across the BBB and / or exhibit increased ability to cross the cell membrane. Transport across the BBB can be achieved by various mechanisms known in the art (e.g., transmembrane diffusion, saturable transporters, adsorbent endocytosis, and extracellular pathways). Transport across the cell membrane is also known in the art (e.g., active or passive transport mechanisms). In some embodiments, molecules or macromolecules can assist in the delivery of active drugs across the BBB and / or cell membrane. Non-limiting examples of substances that cross the blood-brain barrier and / or enhance cell permeability are described herein. 【0089】 The term “substitutable atom” refers to an atom that can be further substituted with a group or moiety as described herein, and in some embodiments, such substitutions cause the compounds described herein to retain activity. It will be understood by those skilled in the art that such groups or moieties are not intended to induce any substitutions or substitution patterns that are sterically impractical, synthetically unrealistic, and / or inherently unstable. 【0090】 compound Compounds that simultaneously bind to both mHTT and ubiquitin E3 ligase are provided herein. Such compounds are intended to promote the ubiquitination and degradation of mHTT. 【0091】 In some embodiments, the simultaneous binding of the compounds described herein to both mHTT and ubiquitin E3 ligase leads to the formation of a ternary complex, followed by the transfer of multiple ubiquitin molecules to mHTT. After dissociation or degradation of the complex, the polyubiquitinated mHTT is to be recognized and degraded by the proteasome. 【0092】 Some embodiments involve compounds of formula (I). WL-ULM (I) Or to provide a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof. (In the formula, W is a compound that targets mutant huntingtin protein (mHTT), L is a connecting portion which is either a bond or, in some cases, is replaced by B. ULM is a region that targets E3 ubiquitin ligase. B is the portion that crosses the blood-brain barrier and / or enhances cell permeability. 【0093】 Some embodiments involve compounds of formula (I). WL-ULM (I) Or provide a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or isotope-enriched analog thereof. (In the formula, W is a compound that targets mutant huntingtin protein (mHTT), L is a connecting portion which is either a bond or, in some cases, is replaced by B. ULM is a region that targets E3 ubiquitin ligase. B is the portion that crosses the blood-brain barrier and / or enhances cell permeability. 【0094】 In some embodiments, the compound of formula (I) 【0095】 [ka] It is not TIFF0007872824000002.tif26141. 【0096】 In some embodiments, the compound of formula (I) comprises a single linkage portion which is optionally substituted with B. 【0097】 Some embodiments provide deuterated analogs of the compound of formula (I). 【0098】 In some embodiments, each of W, L, and ULM of the compound of formula (I) can bond to any possible substituent to form the compound of formula (I). In some embodiments, the substituteable atom of W bonds to the substituteable atom of L (e.g., covalently). In some embodiments, the substituteable atom of L bonds to the substituteable atom of ULM (e.g., covalently). 【0099】 In some embodiments, the compound of formula (I) WL-ULM (I) Alternatively, a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or isotope-enriched analog thereof is provided in the present invention. (In the formula, L is a connecting part that is sometimes replaced by B, ULM 【0100】 [ka] It is TIFF0007872824000004.tif52162, W is (i) Compound of formula (A) 【0101】 [ka] (In the formula, the bond site of W to L-ULM is any of the substitutable atoms in formula (A)), (ii) Compounds of formula (B) 【0102】 [ka] (In the formula, the bond site of W to L-ULM is any of the substitutable atoms in formula (B)), Alternatively, the compound of formula (iii) (E) 【0103】 [ka] (In the formula, the bond site of W to L-ULM is any of the substitutable atoms in formula (E).) And, The variable elements of formulas (A), (B), and (E) are as described herein. 【0104】 Typical W section In some embodiments, W is a compound that binds to mutant huntingtin protein (mHTT). 【0105】 It is intended that even after W is conjugated to L-ULM, the compound of formula (I) retains its activity and is capable of binding to mHTT. In some embodiments, even after W is conjugated to L-ULM, the compound of formula (I) retains at least 50% activity, at least 60% activity, at least 70% activity, at least 80% activity, at least 90% activity, or at least 95% activity compared to W before conjugation to L-ULM. 【0106】 In some embodiments, W is a compound of formula (A). 【0107】 [ka] (In the formula, The bond site of W to L-ULM is any substitutable atom in formula (A), L1 is either -CH=CH- or L1 does not exist. R1 is selected from phenyl or heteroaryl, each of which is Cyano, Hello, Heteroaryl, Lower alkyl, Lower alkoxy substituted with heteroaryl Lower alkyl groups substituted with one or two substituents independently selected from the above, -C(O)O- Lower alkyl, Hydroxyl, Lower alkynyl oxy, Lower alkoxys, and Hello, Heterocycloalkyl, Heteroaryl, Heteroaryls substituted with lower alkoxys, In some cases, the amino acids are substituted. Alkyls substituted with heteroaryls, and Alkyls substituted with lower alkoxys and heteroaryls Lower alkoxy substituted with one or two substituents independently selected from It is optionally replaced by one, two, or three elements independently selected from the above, or R1 is a phenyl compound substituted with two groups, which together with the carbon atom to which they are bonded form a heterocycloalkenyl ring, and this phenyl compound is Hello, Heteroaryls, and In some cases, the amino acids are substituted. They are further optionally substituted with substituents selected from, L2 is either -N(R4)- or L2 does not exist. R2 is hydrogen, Lower alkyl, and Lower alkyl groups substituted with lower alkoxy, amino, (alkyl)amino, (dialkyl)amino, or hydroxyl. Selected from, Each time it appears, R3 Hello, Cyano, Lower alkoxy, Lower alkyl groups optionally substituted with amino, (alkyl)amino or di(alkyl)amino, and Ethynyl may be substituted with tri(alkyl)silyl. Selected independently from, R4 is hydrogen or a lower alkyl group. m is 0, 1, or 2. That is the case. 【0108】 In some embodiments, W is a compound of formula (B). 【0109】 [ka] (In the formula, The bond site of W to L-ULM is any substitutable atom in formula (B), Z1, Z2, Z3, and Z4 are selected independently of CH and N, provided that at least two of Z1, Z2, Z3, and Z4 are CH. R5 is a heteroaryl, heterocycloalkenyl, or heterocycloalkyl group, each of which is optionally substituted with one or two groups independently selected from cyano, halo, lower alkyl (optionally substituted with amino, alkylamino, or di(alkyl)amino), lower alkoxy (optionally substituted with lower alkoxy), optionally substituted amino, haloalkyl, di(alkyl)aminocarbonyl, alkylaminocarbonyl, and aminocarbonyl groups. or R5 is a phenyl optionally substituted with one or two groups independently selected from cyano, heteroaryl, halo, phenoxy, benzyloxy, heteroaryl, amino, (alkyl)amino or di(alkyl)amino lower alkyl, lower alkoxy, optionally substituted amino, di(alkyl)aminocarbonyl, alkylaminocarbonyl, and aminocarbonyl groups. L3 is -O- and L4 is -(CR8R9) p -or-(CR8R9) p -O- or L3 is -NR 10 - and L4 is -C(O)- or -(R8R9) p - and, or L3 is -NR 10 - and L4 is -C(O)(O)(R8R9) p - and, or L3 is -NR 10- and L4 is -C(O)(R8R9) p (O)- and, or L3 is -NR 10 - and L4 is -C(O)(R8R9) p - and, or L3 is -NR 10 - and L4 is -C(O)CR8=CR9-, or L3 is -C(O)- and L4 is -NR 10 - and, or L3 is -(R8R9) p - and L4 is -NR 10 -, -C(O)- or -O-, or L3 does not exist, L4 does not exist, or L3, together with L4, is -CH=CH-, -C≡C-, or heterocyclylene. L5 is either -CH=CH- or L5 does not exist. R6 is selected from heterocycloalkyl, aryl, and heteroaryl, each of which is -OC(O)-R 11 , -C(O)OR 11 , amino, Hello, Haloalkyl, Phenyl, Heteroaryl, Cyano, (lower alkyl) thio, Phenoxy, Phenoxymethyl, Heteroaryloxy, Heteroaryloxys substituted with lower alkyl groups, Hydroxyl, Lower alkenyl oxy, Lower alkoxy, Lower alkoxys, aminos, (alkyl)aminos, (dialkyl)aminos, heterocycloalkyls, heteroaryls, or lower alkoxys substituted with halos, Lower alkyl, and Lower alkyl groups substituted with amino, (alkyl)amino, (dialkyl)amino, hydroxyl, or lower alkoxy groups. Optionally replaced by one or two bases selected from, X1 is NR 12 , O or S, Y1 is CR 12 or N, R 10 is hydrogen or a lower alkyl group. R 12 is hydrogen, halo, cyano, or lower alkyl, Each R7 is independently selected from lower alkyl, lower alkoxy, and halo. R 11 It is a lower alkyl group, Each R8 is independently selected from hydrogen, hydroxyl, trifluoromethyl, and lower alkyl. Each R9 is independently selected from hydrogen and lower alkyl groups. n is either 0 or 1. p is 0, 1, or 2. That is the case. 【0110】 In some embodiments, W is a compound of formula (B)(i). 【0111】 [ka] (In the equation, the dashed line represents the connection point of L-ULM to L.) 【0112】 In some embodiments, W is a compound of formula (B)(i)(a). 【0113】 [ka] (In the equation, the dashed line represents the connection point of L-ULM to L.) 【0114】 In some embodiments, W is a compound of formula (B)(ii). 【0115】 [ka] (In the equation, the dashed line represents the connection point of L-ULM to L.) 【0116】 In some embodiments, W is a compound of formula (B)(ii)(a). 【0117】 [ka] (In the equation, the dashed line represents the connection point of L-ULM to L.) 【0118】 In some embodiments, R5 is a heteroaryl group optionally substituted with one or two groups independently selected from cyano, halo, lower alkyl (optionally substituted with amino, alkylamino, or di(alkyl)amino), lower alkoxy, optionally substituted amino, haloalkyl, di(alkyl)aminocarbonyl, alkylaminocarbonyl, and aminocarbonyl. 【0119】 In some embodiments, R5 is a heterocycloalkenyl optionally substituted with one or two groups independently selected from cyano, halo, lower alkyl (optionally substituted with amino, alkylamino or di(alkyl)amino), lower alkoxy, optionally substituted amino, haloalkyl, di(alkyl)aminocarbonyl, alkylaminocarbonyl, and aminocarbonyl. 【0120】 In some embodiments, R5 is a heterocycloalkyl group optionally substituted with one or two groups independently selected from cyano, halo, lower alkyl (optionally substituted with amino, alkylamino, or di(alkyl)amino), lower alkoxy, optionally substituted amino, haloalkyl, di(alkyl)aminocarbonyl, alkylaminocarbonyl, and aminocarbonyl groups. 【0121】 In some embodiments, R6 is a 5-6 member heteroaryl, each of which is optionally substituted with one or two groups selected from halo; lower alkoxy; lower alkoxy, amino, (alkyl)amino, (dialkyl)amino, heterocycloalkyl, heteroaryl or halo-substituted lower alkoxy; lower alkyl, and lower alkyl substituted with amino, (alkyl)amino, (dialkyl)amino, hydroxyl or lower alkoxy. 【0122】 In some embodiments, W is a compound of formula (C). 【0123】 [ka] (In the formula, The bond site of W to L-ULM is any substitutable atom in formula (C), X2 (CR 16 =CR 16 ), O, NH or S, Y2 is CR 16 or N, Each R 16 This is independently selected from hydrogen, halo, cyano, and lower alkyl, Z1, Z2, Z3, and Z4 are selected independently of CH and N, provided that at least two of Z1, Z2, Z3, and Z4 are CH. R 13 is an aryl, heteroaryl, or heterocycloalkyl group, each of which is optionally substituted with one or two groups independently selected from alkynyl, heteroaryl, cyano, optionally substituted amino, halo, and optionally substituted amino-substituted lower alkyl groups. L6 does not exist, or is C(O)O, O, or NR 17 And, R 17 is hydrogen or a lower alkyl group. L7 is (CH2) q And, R 14These are hydrogen, hydroxyl, lower alkyl, lower haloalkyl, halo, or lower alkoxy, Each R 15 is selected from lower alkyl, lower alkoxy and halo, or R 14 and R 15 It combines with any atom in between to form a 5-7 membered heterocycloalkyl ring. z is either 0 or 1. (q is 0, 1, or 2) That is the case. 【0124】 In some embodiments, W is a compound of formula (D). 【0125】 [ka] (In the formula, The bond site of W to L-ULM is any substitutable atom in formula (D), Z1, Z2, Z3, and Z4 are selected independently of CH and N, provided that at least two of Z1, Z2, Z3, and Z4 are CH. R 18 is an aryl, heteroaryl, or heterocycloalkenyl, each of which is optionally substituted with one or two groups independently selected from alkynyl, heteroaryl, cyano, optionally substituted amino, halo, lower alkyl, and optionally substituted amino lower alkyl groups. L8 is O or NR 21 And, R 21 is hydrogen or a lower alkyl group. L9 is (CH2) x And, R 19 These are aryl, heteroaryl, and heteroaryl substituted with hydrogen, aryl, hydroxyl, or lower alkoxy. Each R 20These are independently selected from lower alkyl, lower alkoxy, halo, and oxo (as substituents on a heterocycloalkyl ring), x is 0, 1, or 2. (y is either 0 or 1) That is the case. 【0126】 In some embodiments, W is a compound of formula (E). 【0127】 [ka] (In the formula, The bond site of W to L-ULM is any substitutable atom in formula (E), J is C (=O) or -CH2-, X3 is either S or N. Y3 is either CH or N. Z5 is CH or N, Q is either N or S. Each time it appears, R 23 The elements are independently selected from halo, lower alkoxy, hydroxy, aryl, heteroaryl, cycloalkoxy, and lower alkyl, and the lower alkoxy, cycloalkoxy, lower alkyl, aryl, or heteroaryl are lower alkoxy, alkenyl, -NR 24 R 25 Each group is optionally substituted with one, two, or three groups independently selected from heteroaryls that are optionally substituted with a halo and one to three lower alkoxys. R 21 is hydrogen or a lower alkyl group. R 22 is alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl or heteroaralkyl, each of which is a lower alkoxy optionally substituted with hydroxy, lower alkoxy or halo, a lower alkyl optionally substituted with halo, halo, heteroaryl, -(CH2) t NR 24 R 25 , oxo, cyano, and -C(O)-NR 24 R25 It may be substituted by one, two, or three elements independently selected from, or R 21 and R 22 These, together with the nitrogen to which they are bonded, form hydroxy, lower alkoxy, lower alkyl, halo, and -C(O)-NR 24 R 25 A heterocycloalkyl ring is formed, optionally substituted with one, two, or three groups independently selected from the above, t is 0, 1, or 2. Each R 24 This is independently selected from hydrogen or a lower alkyl group. Each R 25 is independently selected from hydrogen or lower alkyl, or R 24 and R 25 These, together with the nitrogen to which they are bonded, form hydroxy, lower alkoxy, lower alkyl, halo, or -C(O)-NR 26 R 27 A heterocycloalkyl ring is formed which is optionally substituted with one, two, or three groups independently selected from the above, Each R 26 These are independently hydrogen or a lower alkyl group. Each R 27 These are independently hydrogen or a lower alkyl group. s is 0, 1, or 2. (r is either 1 or 2) That is the case. 【0128】 In some embodiments, W is a compound of formula (E)(i). 【0129】 [ka] (In the equation, the dashed line represents the connection point of L-ULM to L.) 【0130】 In some embodiments, R 21 is hydrogen, R 22is an aryl, aralkyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl or heteroaralkyl, each of which is a lower alkoxy optionally substituted with a hydroxyl, lower alkoxy or halo, a lower alkyl optionally substituted with a halo, a halo, a heteroaryl, -(CH2) t NR 24 R 25 , oxo, cyano, and -C(O)-NR 24 R 25 It is optionally replaced by one, two, or three elements selected independently of it. 【0131】 In some embodiments, W is a compound of formula (F). 【0132】 [ka] (In the formula, X3 is either S or N. Y3 is either CH or N. Z5 is CH or N, Q is either N or S. R 28 These include cyano, lower alkoxy, lower alkenyl, and -NR. 24 R 25 A heteroaryl molecule optionally substituted with 1, 2, or 3 groups, independently selected from a halo and a heteroaryl molecule optionally substituted with 1 to 3 lower alkoxy groups. Each R 24 This is independently selected from hydrogen or a lower alkyl group. Each R 25 is independently selected from hydrogen or lower alkyl, or R 24 and R 25 These, together with the nitrogen to which they are bonded, form hydroxy, lower alkoxy, lower alkyl, halo, or -C(O)-NR 26 R 27 A heterocycloalkyl ring is formed which is optionally substituted with one, two, or three groups independently selected from the above, Each R 26These are independently hydrogen or a lower alkyl group. Each R 27 These are independently hydrogen or a lower alkyl group. The wavy line represents the connection point of W to L in L-ULM. That is the case. 【0133】 In some embodiments, R 28 These include cyano, lower alkoxy, lower alkenyl, and -NR. 24 R 25 It is a bicyclic heteroaryl, optionally substituted with one, two, or three groups independently selected from heteroaryls optionally substituted with a halo and one to three lower alkoxy groups. 【0134】 In some embodiments, R 28 cyano and -NR 24 R 25 It is a biring heteroaryl, optionally substituted with one or two groups independently selected from the original. 【0135】 In some embodiments, W is bonded to L of L-ULM by an optional substitute atom, 2-(5-fluoro-1-benzofuran-2-yl)-N-methylimidazo[1,2-a]pyridine-3-amine; 2-(5-methoxy-1-benzofuran-2-yl)-N-methylimidazo[1,2-a]pyridine-3-amine; 6-fluoro-2-(5-methoxy-1-benzofuran-2-yl)-N-methylimidazo[1,2-a]pyridine-3-amine; 7-Fluoro-2-(5-methoxy-1-benzofuran-2-yl)-N-methylimidazo[1,2-a]pyridine-3-amine; 2-(5-methoxy-1-benzofuran-2-yl)-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 2-[6-fluoro-3-(methylamino)imidazo[1,2-a]pyridine-2-yl]-1-benzofuran-5-ol; 2-(5-methoxy-1-benzofuran-2-yl)-N-(2-methoxyethyl)imidazo[1,2-a]pyridine-3-amine; 2-[7-fluoro-3-(methylamino)imidazo[1,2-a]pyridine-2-yl]-1-benzofuran-5-ol; 2-{3-[(2-hydroxyethyl)amino]imidazo[1,2-a]pyridine-2-yl}-1-benzofuran-5-ol; 2-(5-hydroxy-1-benzofuran-2-yl)-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 2-[5-(2-fluoroethoxy)-1-benzofuran-2-yl]-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 2-(4-methoxyphenyl)-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 2-(6-methoxy-1-benzofuran-2-yl)-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 7-Methoxy-2-(5-Methoxy-1-benzofuran-2-yl)-N-methylimidazo[1,2-a]pyridine-3-amine; 3-(methylamino)-2-[3-(pyridine-3-ylmethoxy)phenyl]imidazo[1,2-a]pyridine-7-carbonitrile; 3-(methylamino)-2-[4-(pyridine-3-ylmethoxy)phenyl]imidazo[1,2-a]pyridine-7-carbonitrile; 7-Chloro-2-(5-methoxy-1-benzofuran-2-yl)-N-methylimidazo[1,2-a]pyridine-3-amine; 7-Bromo-2-(5-methoxy-1-benzofuran-2-yl)-N-methylimidazo[1,2-a]pyridine-3-amine; 2-(5-methoxy-1-benzofuran-2-yl)-3-(methylamino)imidazo[1,2-a]pyridine-6-carbonitrile; 2-(5-bromo-1-benzofuran-2-yl)-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 3-(methylamino)-2-[3-(pyrazine-2-yl)phenyl]imidazo[1,2-a]pyridine-7-carbonitrile; 3-(methylamino)-2-[4-(pyrazine-2-yl)phenyl]imidazo[1,2-a]pyridine-7-carbonitrile; 2-[(E)-2-(4-methoxyphenyl)ethenyl]-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 2-(5-methoxy-1-benzofuran-2-yl)-3-[(2-methoxyethyl)amino]imidazo[1,2-a]pyridine-7-carbonitrile; 2-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 2-(5-bromofuran-2-yl)-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 2-(4-cyanophenyl)-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitriel; 2-(1-benzofuran-5-yl)-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitriel; 3-(methylamino)-2-[4-(propa-2-in-1-yloxy)phenyl]imidazo[1,2-a]pyridine-7-carbonitrile; 2-(5-fluoro-1-benzofuran-2-yl)-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 2-{3-[(5-methoxypyrazine-2-yl)methoxy]phenyl}-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 2-{5-[(5-methoxypyrazine-2-yl)methoxy]pyridine-2-yl}-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 3-(dimethylamino)-2-(5-methoxy-1-benzofuran-2-yl)imidazo[1,2-a]pyridine-7-carbonitrile; 2-(5-methoxy-1-methyl-1H-1,3-benzodiazole-2-yl)-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 2-(6-methoxy-1,3-benzothiazole-2-yl)-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 2-(5-methoxy-1,3-benzoxazol-2-yl)-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 2-(5-methoxy-1H-1,3-benzodiazole-2-yl)-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 2-(5-methoxy-1-benzofuran-2-yl)imidazo[1,2-a]pyridine-7-carbonitriel; 2-(6-methoxy-1-methyl-1H-1,3-benzodiazole-2-yl)-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitriel; 3-(methylamino)-2-[5-(pyridine-3-ylmethoxy)-1-benzofuran-2-yl]imidazo[1,2-a]pyridine-7-carbonitrile; 3-amino-2-[5-(2-fluoroethoxy)-1-benzofuran-2-yl]imidazo[1,2-a]pyridine-7-carbonitrile; 3-amino-2-(5-methoxy-1-benzofuran-2-yl)imidazo[1,2-a]pyridine-7-carbonitriel; 2-(5-methoxy-1-benzofuran-2-yl)-3-(methoxymethyl)imidazo[1,2-a]pyridine-7-carbonitrile; 3-[(dimethylamino)methyl]-2-(5-methoxy-1-benzofuran-2-yl)imidazo[1,2-a]pyridine-7-carbonitrile; 2-{5-[2-(dimethylamino)ethoxy]-1-benzofuran-2-yl}-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitriel; 3-(methylamino)-2-{4-[(pyridine-3-ylmethoxy)methyl]phenyl}imidazo[1,2-a]pyridine-7-carbonitrile; 3-{[2-(dimethylamino)ethyl]amino}-2-(5-methoxy-1-benzofuran-2-yl)imidazo[1,2-a]pyridine-7-carbonitrile tert-butyl2-[7-cyano-3-(methylamino)imidazo[1,2-a]pyridine-2-yl]-4H,5H,6H,7H-fl[3,2-c]pyridine-5-carboxylate; 7-(aminomethyl)-2-(5-methoxy-1-benzofuran-2-yl)-N-methylimidazo[1,2-a]pyridine-3-amine; 3-(methylamino)-2-{3-[(pyridine-3-ylmethoxy)methyl]phenyl}imidazo[1,2-a]pyridine-7-carbonitrile; 2-{4-[(5-methoxypyrazine-2-yl)methoxy]phenyl}-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 2-{6-[(5-methoxypyrazine-2-yl)methoxy]pyridine-3-yl}-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 2-(5-methoxy-1-benzofuran-2-yl)-N-methyl-7-[2-(trimethylsilyl)ethynyl]imidazo[1,2-a]pyridine-3-amine; 7-Ethinyl-2-(5-methoxy-1-benzofuran-2-yl)-N-methylimidazo[1,2-a]pyridine-3-amine; 2-(4-{[(5-methoxypyridine-2-yl)methyl]amino}phenyl)-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 2-(4-{5H,6H-imidazo[2,1-b][1,3]thiazole-3-ylmethoxy}phenyl)-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 2-{10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0 2,6]Dodeca-1(12),3,5,8,10-pentaen-4-yl}-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 2-{11-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]Dodeca-1(12),3,5,8,10-pentaen-4-yl}-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; and 2-{5-[(5-methoxypyridine-2-yl)methoxy]pyrazine-2-yl}-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile It is a compound selected from among them. 【0136】 In some embodiments, W is bonded to L of L-ULM by an optional substitute atom, tert-butyl 4-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]piperazine-1-carboxylate, 4-Methoxy-N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]benzamide; 4-Methoxy-N-[2-(pyridine-4-yl)-1,3-benzoxazole-5-yl]benzamide; N-[(4-methoxyphenyl)methyl]-2-(pyridine-3-yl)-1,3-benzoxazole-5-amine; 2-(3-bromopyridine-4-yl)-6-[2-(morpholine-4-yl)ethoxy]-1,3-benzothiazole; 5-Methoxy-N-[2-(3-methylphenyl)-1,3-benzoxazole-5-yl]pyridine-2-carboxamide; 6-Methoxy-N-[2-(3-methylphenyl)-1,3-benzoxazole-5-yl]pyridine-3-carboxamide; 2-Methoxy-N-[2-(3-methylphenyl)-1,3-benzoxazole-5-yl]pyrimidine-5-carboxamide; 5-Methoxy-N-[2-(3-methylphenyl)-1,3-benzoxazole-5-yl]pyrazine-2-carboxamide; 4-Methoxy-N-[2-(3-methylphenyl)-[1,3]oxazolo[5,4-b]pyridine-6-yl]benzamide; 5-(4-methoxyphenyl)-2-(pyridine-3-yl)-1,3-benzoxazole; N-(4-methoxyphenyl)-2-(pyridine-3-yl)-1,3-benzoxazole-5-amine; 2-(pyridine-3-yl)-N-{[1,2,4]triazolo[4,3-a]pyridine-3-yl}-1,3-benzoxazole-5-amine; 2-(pyridine-3-yl)-N-(pyrimidine-4-yl)-1,3-benzoxazole-5-amine; 2-(pyridine-3-yl)-N-(pyrimidine-2-yl)-1,3-benzoxazole-5-amine; 5-(5-methoxypyridine-2-yl)-2-(pyridine-3-yl)-1,3-benzoxazole; 5-(2-methoxypyrimidine-5-yl)-2-(pyridine-3-yl)-1,3-benzoxazole; 5-(5-methoxypyrimidine-2-yl)-2-(pyridine-3-yl)-1,3-benzoxazole; 5-(6-methoxypyridazine-3-yl)-2-(pyridine-3-yl)-1,3-benzoxazole; 5-(5-methoxypyrazine-2-yl)-2-(pyridine-3-yl)-1,3-benzoxazole; 1-Methyl-4-[5-(pyrimidine-5-ylmethoxy)-1-benzofuran-2-yl]-1H-pyrazole-3-carbonitrile; 4-[5-(pyrimidine-5-ylmethoxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile; 4-{5-[(5-methoxypyridine-2-yl)methoxy]-1-benzofuran-2-yl}pyridine-3-carbonitrile; 4-{5-[(5-methoxypyridine-2-yl)methoxy]-1-benzofuran-2-yl}pyridine; 4-{5-[(1-methyl-1H-imidazole-4-yl)methoxy]-1-benzofuran-2-yl}pyridine-3-carbonitrile; 4-{5-[(1-methyl-1H-imidazole-2-yl)methoxy]-1-benzofuran-2-yl}pyridine-3-carbonitrile; 5-Methoxy-2-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]-2,3-dihydro-1H-isoindole-1-one; 3-{6-[(E)-2-(4-methoxyphenyl)ethenyl]-[1,3]oxazolo[5,4-b]pyridine-2-yl}pyridine; 4-[5-(pyridine-3-yloxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile; 6-methoxy-2-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]-1,2,3,4-tetrahydroisoquinoline-1-one; Dimethyl({3-[4-({[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]oxy}methyl)phenoxypropyl})amine; 5-[(1-methyl-1H-pyrazole-4-yl)methoxy]-2-(pyridine-3-yl)-1,3-benzoxazole; 5-[(4-methoxyphenyl)methoxy]-2-(pyridine-3-yl)-1,3-benzoxazole; 5-[(3-methoxyphenyl)methoxy]-2-(pyridine-3-yl)-1,3-benzoxazole; 5-[(5-methoxypyridine-2-yl)methoxy]-2-(pyridine-3-yl)-1,3-benzoxazole; 2-(pyridine-3-yl)-5-(pyridine-3-ylmethoxy)-1,3-benzoxazole; 5-{5H,6H-imidazo[2,1-b][1,3]thiazole-3-ylmethoxy}2-(pyridine-3-yl)-1,3-benzoxazole; 1-(pyridine-2-yl)-2-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]ethane-1-ol; 1-(pyridine-2-yl)-2-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]ethane-1-one; 6-Methoxy-2-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]-1,2-dihydroisoquinoline-1-one; 2-(pyridine-3-yl)-N-[2,2,2-trifluoro-1-(4-methoxyphenyl)ethyl]-[1,3]oxazolo[5,4-b]pyridine-6-amine; 3-{6-[2-(4-methoxyphenyl)ethynyl]-[1,3]oxazolo[5,4-b]pyridine-2-yl}pyridine; 3-{6-[(Z)-2-(4-methoxyphenyl)ethenyl]-[1,3]oxazolo[5,4-b]pyridine-2-yl}pyridine; 5-Methoxy-2-[2-(pyridine-3-yl)-[1,3]oxazolo[5,4-b]pyridine-6-yl]-2,3-dihydro-1H-isoindole-1-one; 5-[(5-methoxypyrazine-2-yl)methoxy]-2-(pyridine-3-yl)-1,3-benzoxazole; 3-Methoxy-6-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridine-7-one; 2-(pyridine-3-yl)-6-(pyridine-3-ylmethoxy)-1,3-benzoxazole; 3-{6-[2-(pyridine-3-yl)ethynyl]-[1,3]oxazolo[5,4-b]pyridine-2-yl}pyridine; 5-{[(5-methoxypyridine-2-yl)oxy]methyl}2-(pyridine-3-yl)-1,3-benzoxazole; 4-[5-(pyridine-3-ylmethoxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile; 4-{5-[(1-methyl-1H-pyrazole-4-yl)methoxy]-1-benzofuran-2-yl}pyridine-3-carbonitrile; 3-[5-(pyridine-3-ylmethoxy)-1-benzofuran-2-yl]pyridine-4-carbonitrile; 3-{5-[(1-methyl-1H-pyrazole-4-yl)methoxy]-1-benzofuran-2-yl}pyridine-4-carbonitrile; 3-{6-[1-(5-methoxypyridine-2-yl)ethoxy]-[1,3]oxazolo[5,4-b]pyridine-2-yl}pyridine; 4-{5-[(5-methoxypyrazine-2-yl)methoxy]-1-benzofuran-2-yl}pyridine-3-carbonitrile; 6-({[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]oxymethyl)pyridine-3-ol; 5-{[5-(propa-2-en-1-yloxy)pyrazine-2-yl]methoxy}2-(pyridine-3-yl)-1,3-benzoxazole; 5-({[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]oxymethyl)-1,2-dihydropyrazine-2-one; 1-Methyl-5-({[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]oxymethyl)-1,2-dihydropyrazine-2-one; 5-[4-(5-methoxypyrimidine-2-yl)piperazine-1-yl]-2-(pyridine-3-yl)-1,3-benzoxazole; 3-{6-[(5-methoxypyridine-2-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridine-2-yl}pyridine; 5-(1-methyl-1H-pyrazole-4-yl)-2-(pyridine-3-yl)-1,3-benzoxazole; 3-{6-[(6-methoxypyridine-3-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridine-2-yl}pyridine; 5-[(5-methoxypyridine-2-yl)methoxy]-2-(pyridine-4-yl)-1,3-benzoxazole; [(3-{5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole-2-yl}phenyl)methyl]dimethylamine; 5-[(5-methoxypyridine-2-yl)methoxy]-2-(1-methyl-1H-pyrazole-4-yl)-1,3-benzoxazole; 5-[(5-methoxypyridine-2-yl)methoxy]-2-(pyrazine-2-yl)-1,3-benzoxazole; 5-[(5-methoxypyridine-2-yl)methoxy]-2-(1-methylpiperidine-4-yl)-1,3-benzoxazole; 5-[(5-methoxypyridine-2-yl)methoxy]-2-(1,3-thiazole-5-yl)-1,3-benzoxazole; 5-[2-(pyridine-2-yloxy)ethoxy]-2-(pyridine-3-yl)-1,3-benzoxazole; 4-[5-(1H-pyrazole-4-ylmethoxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile; 3-{[(2-{5H,6H-imidazo[2,1-b][1,3]thiazole-3-yl}-1-benzofuran-5-yl)oxy]methyl}pyridine; 2-(3-fluoroazetidine-1-yl)-5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole; 2-{3H,4H,5H,6H,7H-imidazo[4,5-c]pyridine-5-yl}-5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole; 5-[(5-methoxypyridine-2-yl)methoxy]-2-{2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-yl}-1,3-benzoxazole; 2-{5H,6H,7H,8H-imidazo[1,5-a]pyrazine-7-yl}-5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole; 5-[(5-methoxypyridine-2-yl)methoxy]-2-{5H,6H,7H-pyrrolo[3,4-b]pyridine-6-yl}-1,3-benzoxazole; 7-{5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole-2-yl}-5,6,7,8-tetrahydro-1,7-naphthyridine; 2-(1H-imidazole-1-yl)-5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole; 2-{5H,6H,7H,8H-imidazo[1,2-a]pyrazine-7-yl}-5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole; 4-(5-{[1-(2-methoxyethyl)-1H-pyrazole-4-yl]methoxy}-1-benzofuran-2-yl)pyridine-3-carbonitrile; 2-[5-(2-methoxyethoxy)pyridine-3-yl]-5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole; N-(5-{5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole-2-yl}pyridine-2-yl)acetamide; 5-{5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole-2-yl}pyridine-2-amine; Methyl({[4-({[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]oxymethyl)phenyl]methyl})amine; 4-(5-{[1-(2-hydroxyethyl)-1H-pyrazole-4-yl]methoxy}-1-benzofuran-2-yl)pyridine-3-carbonitrile; Dimethyl({2-[4-({[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]oxy}methyl)phenoxyethyl})amine; 5-{[5-(2-methoxyethoxy)pyridine-2-yl]methoxy}2-(pyridine-3-yl)-1,3-benzoxazole; 4-[5-({1-[2-(dimethylamino)ethyl]-1H-pyrazole-4-yl}methoxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile; 5-{5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole-2-yl}-N-methylpyridine-2-amine; 3-{[(2-{2-bromo-5H,6H-imidazo[2,1-b][1,3]thiazole-3-yl}-1-benzofuran-5-yl)oxy]methyl}pyridine; 5-[(5-methoxypyrazine-2-yl)methoxy]-1-methyl-2-(pyridine-3-yl)-1H-1,3-benzodiazole; 6-[(5-methoxypyrazine-2-yl)methoxy]-1-methyl-2-(pyridine-3-yl)-1H-1,3-benzodiazole; 5-[(5-methoxypyrazine-2-yl)methoxy]-2-(pyridine-3-yl)-1H-1,3-benzodiazole; 5-[(5-methoxypyridine-2-yl)methoxy]-2-(piperazine-1-yl)-1,3-benzoxazole; N-methyl-6-({[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]oxy}methyl)pyridine-3-amine; 3-[5-(pyridine-3-ylmethoxy)-1-benzofuran-2-yl]-5H,6H-imidazo[2,1-b][1,3]thiazole-2-carbonitrile; 5-{5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole-2-yl}-N-methylpyridine-2-carboxamide; 5-[(5-methoxypyridine-2-yl)methoxy]-2-(1-methyl-1H-imidazole-4-yl)-1,3-benzoxazole; 5-Methoxy-N-{[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]methyl}pyridine-2-amine; 4-(5-{5H,6H-imidazo[2,1-b][1,3]thiazole-3-ylmethoxy}1-benzofuran-2-yl)pyridine-3-carbonitrile; 5-({5-[2-(morpholine-4-yl)ethoxy]pyridine-2-yl}methoxy)-2-(pyridine-3-yl)-1,3-benzoxazole; 2-bromo-6-{5-[(5-methoxypyridine-2-yl)methoxy]-1-benzofuran-2-yl}benzonitrile; 4-{[2-(4-chlorophenyl)-1,3-benzoxazole-5-yl]carbamoyl}phenylacetate; N-(2-phenyl-1,3-benzoxazol-5-yl)benzamide; 4-Methoxy-N-[2-(3-methylphenyl)-1,3-benzoxazol-5-yl]benzamide; 2-Methoxy-N-[2-(4-methoxyphenyl)-1,3-benzoxazol-5-yl]benzamide; 4-Methoxy-N-[2-(4-methoxyphenyl)-1,3-benzoxazole-5-yl]benzamide; 3-Methoxy-N-[2-(4-methoxyphenyl)-1,3-benzoxazole-5-yl]benzamide; 3-{5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole-2-yl}pyridine-1-ium-1-oleate; 2-Phenoxy-N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]acetamide; N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]-1-benzofuran-2-carboxamide; N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]-6-(trifluoromethyl)pyridine-3-carboxamide; N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]quinoxaline-2-carboxamide; 6-Phenoxy-N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]pyridine-3-carboxamide; N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]-2H-1,3-benzodioxol-5-carboxamide; 3-(benzyloxy)-N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]benzamide; 3-Phenoxy-N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]benzamide; N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]quinoline-2-carboxamide; N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]-2,3-dihydro-1-benzofuran-2-carboxamide; 5-methyl-N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]pyridine-3-carboxamide; N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]quinoxaline-6-carboxamide; (2E)-3-(4-methoxyphenyl)-N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]propa-2-enamide; 5-Methoxy-N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]pyridine-2-carboxamide; 3-Cyano-N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]benzamide; 4-(methylsulfanyl)-N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]benzamide; Benzyl N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]carbamate, 5-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]pyrazine-2-ol; 5-[(5-methoxypyridine-2-yl)methoxy]-2-(pyrimidine-5-yl)-1,3-benzoxazole; 2-(2,3-dihydro-1-benzofuran-2-yl)-5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole; 2-[(2R)-2,3-dihydro-1-benzofuran-2-yl]-5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole; 2-[(2S)-2,3-dihydro-1-benzofuran-2-yl]-5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole; 5-[5-(2-methoxyethoxy)pyrimidine-2-yl]-2-(pyridine-3-yl)-1,3-benzoxazole; 5-[(5-methoxypyridine-2-yl)methoxy]-2-(5-methylpyridine-3-yl)-1,3-benzoxazole; 5-[(5-methoxypyridine-2-yl)methoxy]-2-(2-methylpyridine-4-yl)-1,3-benzoxazole; 5-[(5-methoxypyridine-2-yl)methoxy]-2-(3-phenoxyphenyl)-1,3-benzoxazole; 6-{5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazol-2-yl}-2-methyl-2,3-dihydropyridazine-3-one; 5-[(5-methoxypyridine-2-yl)methoxy]-2-(pyridazine-3-yl)-1,3-benzoxazole; 5-[(5-methoxypyridine-2-yl)methoxy]-2-(pyridazine-4-yl)-1,3-benzoxazole; 5-{5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole-2-yl}-1,2-dihydropyridine-2-one; 5-{5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazol-2-yl}-1-methyl-1,2-dihydropyridine-2-one; 5-phenyl-N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]-1,3,4-oxadiazole-2-carboxamide; 5-[(5-methoxypyridine-2-yl)methoxy]-2-(pyrimidine-4-yl)-1,3-benzoxazole; 5-[(5-bromopyridine-2-yl)methoxy]-2-(pyridine-3-yl)-1,3-benzoxazole; 5-(pyridine-2-ylmethoxy)-2-(pyridine-3-yl)-1,3-benzoxazole; N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]-1-benzofuran-5-carboxamide; 2-phenyl-N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]pyrimidine-5-carboxamide; N-[2-(pyridin-3-yl)-1,3-benzoxazole-5-yl]-4-(pyrimidine-2-yl)benzamide; 1-Methyl-N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]-1H-pyrazole-4-carboxamide; 4-[(6-methylpyrazine-2-yl)oxy]-N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]benzamide; 4-(phenoxymethyl)-N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]benzamide; 2-Phenoxy-N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]pyridine-3-carboxamide; 4-Cyano-N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]benzamide; 6-Methoxy-N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]pyridine-2-carboxamide; 2-methyl-N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]pyridine-4-carboxamide; 3-Methoxy-N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]pyridine-2-carboxamide; 4-Methoxy-N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]pyridine-2-carboxamide; 4-hydroxy-N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]pyridine-2-carboxamide; 3-Methoxy-N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]-1,2-oxazole-5-carboxamide; 5-Methoxy-N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]pyridine-3-carboxamide; 6-({[2-(1-methyl-1H-pyrazole-4-yl)-1,3-benzoxazole-5-yl]oxy}methyl)pyridine-3-ol; 5-[(5-methoxypyrazine-2-yl)methoxy]-2-(1-methyl-1H-pyrazole-4-yl)-1,3-benzoxazole; 2-Methoxy-5-({[2-(1-methyl-1H-pyrazole-4-yl)-[1,3]oxazolo[5,4-b]pyridine-6-yl]oxy}methyl)pyrazine; 3-{6-[(5-bromopyridine-2-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridine-2-yl}pyridine; 3-Methoxy-6-({[2-(pyridine-3-yl)-[1,3]oxazolo[5,4-b]pyridine-6-yl]oxy}methyl)pyridazine; 3-{5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole-2-yl}benzonitrile; 4-{5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole-2-yl}benzonitrile; 5-(1-methyl-1H-pyrazole-4-yl)-2-({[2-(pyridine-3-yl)-[1,3]oxazolo[5,4-b]pyridine-6-yl]oxy}methyl)pyridine; 3-Methoxy-5-({[2-(pyridine-3-yl)-[1,3]oxazolo[5,4-b]pyridine-6-yl]oxy}methyl)pyridine; 4-Methoxy-2-({[2-(pyridine-3-yl)-[1,3]oxazolo[5,4-b]pyridine-6-yl]oxy}methyl)pyridine; 2-({[2-(1-methyl-1H-pyrazole-4-yl)-[1,3]oxazolo[5,4-b]pyridine-6-yl]oxy}methyl)pyrazine; [(3-{5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole-2-yl}phenyl)methyl](methyl)amine; (5-methoxypyridine-2-yl)methyl N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]carbamate; 2-(5-methoxypyridine-2-yl)-5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole; 2-(1-benzofuran-2-yl)-5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole; 5-[(5-methoxypyridine-2-yl)methoxy]-2-[6-(trifluoromethyl)pyridine-3-yl]-1,3-benzoxazole; 2-(1-benzofuran-5-yl)-5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole; 2-{5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole-2-yl}quinoline; 2-[3-(benzyloxy)phenyl]-5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole; 5-[(5-methoxypyridine-2-yl)methoxy]-2-[4-(pyrimidine-2-yl)phenyl]-1,3-benzoxazole; 2-[(E)-2-(4-methoxyphenyl)ethenyl]-5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole; 5-Methoxy-2-({[2-(pyridine-3-yl)-[1,3]oxazolo[5,4-b]pyridine-6-yl]oxy}methyl)pyrimidine; 6-({[2-(1-methyl-1H-pyrazole-4-yl)-[1,3]oxazolo[5,4-b]pyridine-6-yl]oxy}methyl)pyridine-3-amine; 5-{5-[(5-hydroxypyridine-2-yl)methoxy]-1,3-benzoxazole-2-yl}-N-methylpyridine-2-carboxamide; 6-{6-[(5-methoxypyridine-2-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridine-2-yl}-2-methyl-2,3-dihydropyridazine-3-one; 2-methyl-6-({[2-(pyridine-3-yl)-[1,3]oxazolo[5,4-b]pyridine-6-yl]oxy}methyl)-2,3-dihydropyridazine-3-one; 2-{6-[(5-methoxypyridine-2-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridine-2-yl}pyrazine; 5-{6-[(5-methoxypyridine-2-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridine-2-yl}-N-methylpyridine-2-carboxamide; 5-{5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazol-2-yl}-1-methyl-1,2-dihydropyrazine-2-one; 6-(6-{[5-(2-fluoroethoxy)pyridine-2-yl]methoxy}-[1,3]oxazolo[5,4-b]pyridine-2-yl)-2-methyl-2,3-dihydropyridazine-3-one; 5-Methoxy-2-({[2-(pyridine-3-yl)-[1,3]oxazolo[5,4-b]pyridine-6-yl]oxy}methyl)pyridine-1-ium-1-oleate; 3-{6-[(5-methoxy-1-oxidepyridine-1-ium-2-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridine-2-yl}pyridine-1-ium-1-oleate; 5-{5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole-2-yl}-2-(methylcarbamoyl)pyridine-1-ium-1-oleate; (5-hydroxypyridine-2-yl)methyl N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]carbamate; 5-Methoxy-N-[2-(1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)-1,3-benzoxazole-5-yl]pyridine-2-carboxamide; 5-Methoxy-N-[2-(1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)-1,3-benzoxazole-5-yl]pyridine-3-carboxamide; 4-Methoxy-N-[2-(1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)-1,3-benzoxazole-5-yl]pyridine-2-carboxamide; 1-Methyl-N-[2-(1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)-1,3-benzoxazole-5-yl]-6-oxo-1,6-dihydropyridazine-3-carboxamide; [(5-{5-[(5-methoxypyridine-2-yl)methoxy]-1,3-benzoxazole-2-yl}pyridine-3-yl)methyl](methyl)amine; 6-{5-[(5-hydroxypyridine-2-yl)methoxy]-1,3-benzoxazol-2-yl}2-methyl-2,3-dihydropyridazine-3-one; and N-(5-methoxypyridine-3-yl)-2-(pyridine-3-yl)-1,3-benzoxazole-5-carboxamide It is a compound selected from among them. 【0137】 In some embodiments, W is bonded to L of L-ULM by an optional substitute atom, 6-Methoxy-2-(pyridine-3-yl)-1,3-benzoxazole; [2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]methanol; 4-[5-(methoxymethoxy)-1-benzofuran-2-yl]-1-methyl-1H-pyrazole-3-carbonitrile; 4-(5-methoxy-1-benzofuran-2-yl)-3-methylpyridine; 3-iodo-4-(5-methoxy-1-benzofuran-2-yl)pyridine; 2-[(dimethylamino)methyl]-6-(5-methoxy-1-benzofuran-2-yl)benzonitrile; 2-bromo-6-(5-methoxy-1-benzofuran-2-yl)benzonitrile; 5-bromo-2-(5-methoxy-1-benzofuran-2-yl)benzonitrile; 4-iodo-6-(5-methoxy-1-benzofuran-2-yl)pyrimidine-5-carbonitrile; 3-(5-hydroxy-1-benzofuran-2-yl)-5H,6H-imidazo[2,1-b][1,3]thiazole-2-carbonitrile; 4-(6-methoxynaphthalene-2-yl)pyridine-3-carbonitrile; 6-Methoxy-2-(2-methoxyphenyl)-1,3-benzothiazole; 4-(6-methoxy-1,3-benzothiazole-2-yl)benzonitrile; 4-(6-methoxy-1H-1,3-benzodiazole-2-yl)pyridine-3-carbonitrile; 6-Methoxy-2-[3-(1H-pyrazole-5-yl)pyridine-4-yl]-1,3-benzothiazole; 4-(6-methoxy-1,3-benzothiazole-2-yl)-N-methylpyridine-3-amine; 4-(6-methoxyquinoline-2-yl)pyridine-3-carbonitrile; 4-(6-methoxy-1,3-benzothiazole-2-yl)pyridine-3-carbonitrile; 4-(5-methoxy-1-benzofuran-2-yl)pyridine-3-carbonitrile; N-[6-(5-methoxy-1-benzofuran-2-yl)pyridine-2-yl]acetamide; 6-(5-methoxy-1-benzofuran-2-yl)pyridine-3-carbonitrile; 4-(1,3-benzothiazole-2-yl)pyridine-3-carbonitrile; 2-(6-methoxy-1,3-benzothiazole-2-yl)benzonitrile; 2-(3-bromopyridine-4-yl)-6-methoxy-1,3-benzothiazole; 2-(3-bromopyridine-4-yl)-1,3-benzothiazole-6-ol; 2-(3-bromopyridine-2-yl)-6-methoxy-1,3-benzothiazole; 2-(6-methoxy-1,3-benzothiazole-2-yl)pyridine-3-carbonitrile; 2-(3-fluoropyridine-4-yl)-6-methoxy-1,3-benzothiazole; 4-[6-(dimethylamino)-1,3-benzothiazole-2-yl]pyridine-3-carbonitrile; 4-(6-methoxy-1,3-benzothiazole-2-yl)pyridine-2-carbonitrile; 2-(6-methoxy-1,3-benzoxazol-2-yl)benzonitrile; N-[4-(6-methoxy-1,3-benzothiazole-2-yl)pyridine-3-yl]acetamide; 2-(3-bromopyridine-4-yl)-6-(2-fluoroethoxy)-1,3-benzothiazole; 4-[6-(2-fluoroethoxy)-1,3-benzothiazole-2-yl]pyridine-3-carbonitrile; 4-(5-methoxy-1,3-benzothiazole-2-yl)pyridine-3-carbonitrile; 4-[6-(trifluoromethyl)-1,3-benzothiazole-2-yl]pyridine-3-carbonitrile; 4-[5-(2-fluoroethoxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile; 3-(6-methoxy-1,3-benzothiazole-2-yl)pyridine-4-carbonitrile; 5-bromo-3-{5-bromofl[2,3-b]pyridine-2-yl}-1,2-dihydropyridine-2-one; 2-{5-methoxyfl[2,3-c]pyridine-2-yl}benzonitrile; 2-{5-bromofl[2,3-b]pyridine-2-yl}benzonitrile; 2-{5-methoxyfl[2,3-b]pyridine-2-yl}benzonitrile; 4-(5-methoxy-1-benzofuran-2-yl)-1H-indazole; 7-(5-methoxy-1-benzofuran-2-yl)-1H-indazole; 4-[5-(methoxymethoxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile; 4-(5-hydroxy-1-benzofuran-2-yl)pyridine-3-carbonitrile; 4-[5-(2-methoxyethoxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile; 2-(5-methoxy-1-benzofuran-2-yl)pyridine-3-carbonitrile; 4-{5-methoxyfl[2,3-c]pyridine-2-yl}pyridine-3-carbonilicate; 4-{6-methoxyfluoro[3,2-b]pyridine-2-yl}pyridine-3-carbonitrile; 4-(3-bromo-5-methoxy-1-benzofuran-2-yl)pyridine; 5-Methoxy-2-(pyridine-4-yl)-1-benzofuran-3-carbonitrile; 4-[5-(2-hydroxyethoxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile; 2-{4,6,10-trioxa-12-azatricyclo[7.3.0.0 3 , 7 Dodeca-1(9),2,7,11-tetraen-11-yl}benzonitrile; 4-{5-[(2-hydroxyethyl)(methyl)amino]-1-benzofuran-2-yl}pyridine-3-carbonitrile; 2-{2-methoxyfl[2,3-d]pyrimidine-6-yl}benzonitrile; 4-(6-methoxy-1,3-benzoxazole-2-yl)pyridine-3-carbonitrile; 3-(5-methoxy-1-benzofuran-2-yl)-5H,6H-imidazo[2,1-b][1,3]thiazole-2-carbonitrile; 3-Ethinyl-4-(5-methoxy-1-benzofuran-2-yl)pyridine; 4-(5-methoxy-3-methyl-1-benzofuran-2-yl)pyridine-3-carbonitrile; 4-[(dimethylamino)methyl]-2-(5-methoxy-1-benzofuran-2-yl)benzonitrile; 2-(3-methylphenyl)-1,3-benzoxazole-5-amine; 2-(pyridine-3-yl)-1,3-benzoxazole-5-amine; 2-(pyridine-4-yl)-1,3-benzoxazole-5-amine; and 2-(3-methylphenyl)-[1,3]oxazolo[5,4-b]pyridine-6-amine It is a compound selected from among them. 【0138】 In some embodiments, W is bonded to L of L-ULM by an optional substitute atom, 2-(5-methoxy-2,3-dihydro-1H-isoindole-2-yl)pyridine-3-carbonitriel; 2-{5-[(5-methoxypyridine-2-yl)methoxy]-2,3-dihydro-1H-isoindole-2-yl}pyridine-3-carbonitriel; 2-[5-(pyrimidine-5-ylmethoxy)-2,3-dihydro-1H-isoindole-2-yl]pyridine-3-carbonitrile; 4-{5-[(5-methoxypyridine-2-yl)methoxy]-2,3-dihydro-1H-isoindole-2-yl}pyridine-3-carbonitrile; 4-(5-methoxy-2,3-dihydro-1H-isoindole-2-yl)pyrimidine-5-carbonitrile; 4-{5-[(5-methoxypyridine-2-yl)methoxy]-2,3-dihydro-1H-isoindole-2-yl}pyrimidine-5-carbonitrile; 4-{5-[(5-hydroxypyridine-2-yl)methoxy]-2,3-dihydro-1H-isoindole-2-yl}pyridine-3-carbonitrile; 4-(5-methoxy-2,3-dihydro-1H-isoindole-2-yl)pyridine-3-carbonilicate; 4-[5-(pyrimidine-5-ylmethoxy)-2,3-dihydro-1H-isoindole-2-yl]pyridine-3-carbonilicate; 5-[(5-methoxypyrazine-2-yl)methoxy]-2-(pyridine-4-yl)-2,3-dihydro-1H-isoindole; 4-[5-(benzyloxy)-2,3-dihydro-1H-isoindole-2-yl]pyrimidine-5-carbonitrile; 4-{5-[(5-hydroxypyridine-2-yl)methoxy]-2,3-dihydro-1H-isoindole-2-yl}pyrimidine-5-carbonitrile; 6-{5-[(5-methoxypyridine-2-yl)methoxy]-2,3-dihydro-1H-isoindole-2-yl}-2-methyl-2,3-dihydropyridazine-3-one; and 5-[(5-methoxypyridine-2-yl)methoxy]-2-(pyridine-4-yl)-2,3-dihydro-1H-isoindole-1-one It is a compound selected from among them. 【0139】 In some embodiments, W is bonded to L of L-ULM by an optional substitute atom, 10-Methoxy-N-(pyridine-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-Methoxy-N-(6-methoxypyridine-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-Methoxy-N-(pyridine-3-ylmethyl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-Methoxy-N-methyl-N-(pyridine-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; N-(1-benzofuran-5-yl)-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-Hydroxy-N-(6-methoxypyridine-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; N-(6-methoxypyridine-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide; N-(6-fluoropyridine-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide; 10-Hydroxy-N-(pyridine-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-Methoxy-N-(5-Methoxypyridine-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-Methoxy-N-(1-methyl-1H-pyrazole-4-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; N-(6-fluoropyridine-3-yl)-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-Methoxy-N-(pyridine-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-Methoxy-N-(5-Methoxypyridine-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-Methoxy-N-[6-(methylcarbamoyl)pyridine-3-yl]-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-Methoxy-4-{1H,2H,3H-pyrrolo[2,3-c]pyridine-1-carbonyl}-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene; 10-Methoxy-N-(6-methylpyridine-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-Methoxy-4-{1-methyl-1H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carbonyl}-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene; 10-Methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-Methoxy-N-(2-methylpyrimidine-5-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; N-[6-(1H-imidazole-1-yl)pyridine-3-yl]-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-Methoxy-N-(pyrimidine-5-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; N-[2-(dimethylamino)ethyl]-10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-Methoxy-N-(2-methoxyethyl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-Methoxy-N-(6-oxo-1,6-dihydropyridine-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-Methoxy-N-[5-(pyridine-3-yl)pyridine-2-yl]-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-Methoxy-N-(6-oxo-1,6-dihydropyridazine-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 5-Methoxy-N-(pyridine-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide; N-[6-(methylcarbamoyl)pyridine-3-yl]-1,8,10-triazatricyclo[7.4.0.0 2,7 Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide; N-(5-methoxypyridine-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide; N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide; N-(6-oxo-1,6-dihydropyridine-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide; N-(pyridine-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide; N-(3-cyanopyridine-4-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide; N-(2-methoxypyridine-4-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide; N-(5,6-dimethoxypyridine-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide; 5-Methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,8,10-triazaltricyclo[7.4.0.0 2,7 Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide; 5-Methoxy-11-{1-methyl-1H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carbonyl}-1,8,10-triazatricyclo[7.4.0.0 2,7 ]Trideca-2(7),3,5,8,10,12-hexaene; 4-Methoxy-N-(5-Methoxypyridine-3-yl)-1,8,10-Triazatricyclo[7.4.0.0 2,7 Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide; 5-Methoxy-N-(5-methoxypyridine-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide; N-[6-(1H-imidazole-1-yl)pyridine-3-yl]-5-methoxy-1,8,10-triazatricyclo[7.4.0.0 2,7 Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide; N-(3-cyanopyridine-4-yl)-5-methoxy-1,8,10-triazatricyclo[7.4.0.0 2,7 Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide; N-(6-oxo-1,6-dihydropyridazine-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide; N-(3-cyano-2-methoxypyridine-4-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide; 5-Methoxy-N-(6-Methoxypyridine-3-yl)-1,8,10-Triazatricyclo[7.4.0.0 2,7 Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide; 10-Methoxy-N-(5-Methoxypyridine-2-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; N-(5-methoxypyridine-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-Methoxy-N-(pyridine-4-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-Methoxy-N-(pyrazine-2-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 3-{10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]Dodeca-1(12),3,5,8,10-pentaene-4-amide}pyridine-1-ium-1-oleate; 10-(2-fluoroethoxy)-N-(pyridine-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(8),3,5,9,11-pentaene-4-carboxamide; N-({10-methoxy-7-thia-2,5-diazatricyclo[6.4.0.02,6 Dodeca-1(12),3,5,8,10-pentaen-4-yl}methyl)pyridine-3-amine; 10-[(5-methoxypyridine-2-yl)methoxy]-N-(5-methoxypyridine-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; N-(1-methyl-6-oxo-1,6-dihydropyridine-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide; 11-Bromo-N-(5-methoxypyridine-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-10-(propa-2-en-1-yloxy)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-Methoxy-N-(5-Methoxypyridine-3-yl)-5-thia-2,7-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,6,8,10-pentaene-4-carboxamide; 10-Methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)-5-thia-2,7-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,6,8,10-pentaene-4-carboxamide; 10-Methoxy-N-(2-methylpyrimidine-5-yl)-5-thia-2,7-diazatricyclo[6.4.0.0 2,6 Dodeca-1(8),3,6,9,11-pentaene-4-carboxamide; N-(1-methyl-2-oxo-1,2-dihydropyrimidine-5-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide; 11-Methoxy-N-(5-methoxypyridine-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 11-Methoxy-N-(1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)-7-thia-2,5,9-triazatricyclo[6.4.0.0 2,6 ] Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; 10-methoxy-N-{3-[(methylamino)methyl]phenyl}-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(8),3,5,9,11-pentaene-4-carboxamide; 10-[(dimethylamino)methyl]-N-(5-methoxypyridine-3-yl)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; N-(5-methoxypyridine-3-yl)-10-phenyl-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 Dodeca-1(12),3,5,8,10-pentaene-4-carboxamide; N,5-Bis(5-methoxypyridine-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide; N,4-Bis(5-methoxypyridine-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide; N-[5-(2-methoxyethoxy)pyridine-3-yl]-1,8,10-triazatricyclo[7.4.0.0 2,7 ]Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide; and N-[6-(2-methoxyethoxy)pyridine-3-yl]-1,8,10-triazatricyclo[7.4.0.0 2,7 Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide It is a compound selected from among them. 【0140】 In some embodiments, W is 【0141】 [ka] (In the equation, the dashed line represents the connection point of L-ULM to L.) Selected from. 【0142】 Typical ULM parts In some embodiments, the ULM is a portion that recognizes a ubiquitin pathway protein. In some embodiments, the ubiquitin pathway protein is an E3 ubiquitin ligase. In some embodiments, the ULM is a portion that binds to the E3 ubiquitin ligase. In some embodiments, the ULM is an E3 ligase ubiquitin recruiter that targets the E3 ubiquitin ligase. 【0143】 Representative ULMs are publicly known in the art (e.g., WO2018 / 102067, which is incorporated herein by reference in its entirety). 【0144】 In some embodiments, ULM is a molecule that binds to mouse double minute two homolog (MDM2), apoptosis protein 1 cell inhibitor (cIAP1), cereblon (CRBN), or von Hippel-Lindau (VHL). Representative such molecules are known in the art (e.g., Gu et al., BioEssays, April 2018, Vol. 40(4):e1700, p. 24, the whole article is incorporated herein by reference). 【0145】 In some embodiments, ULM is a compound of formula (VIII). 【0146】 [ka] (a is 1, 2, or 3, X A and X B Each of these is independently linked, O, NR B , CR B R C Selected from C=O, C=S, SO and SO2, R B and R C These are, independently, hydrogen and C 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6 Selected from alkoxy, Each R A These are H, halo, OH and C 1~3 Selected independently of alkyl, W A -T(NR D1 R D2 ), -T(NR D1 R D2 )X C -T-aryl, optionally substituted T-heteroaryl, optionally substituted -T-heterocyclic, optionally substituted -NR D -T-aryl, sometimes replaced by -NR D -T-heteroaryl or -NR D-T- is a complex algebra where T is X A It is covalently bonded to it, X C C=O, R D , R D1 or R D2 And, R D , R D1 and R D2 Each of these is independently substituted with hydrogen, 1 to 3 halos, or optionally with OH groups. 1~6 Alkyl, R B C=O, R B C=S, R B SO, R B SO2, N(R B R C )C=O, N(R B R C )C=S, N(R B R C )SO and N(R B R C ) Selected from SO2, T is a bond or C which is optionally substituted with 1 to 5 halo or OH groups. 1~12 Alkyl, or optionally substituted, amino acid side chains, W B -NR is sometimes replaced D4 -T-aryl, sometimes replaced by -NR D4 -T-heteroaryl or -NR D4 It is a -T-heterogene and -NR D4 is X B It is covalently bonded to it, R D4 is hydrogen or C 1~3 It is alkyl, ULM is bonded to WL by any substitutable atom of ULM and L. 【0147】 In some embodiments, ULM is formula 【0148】 [ka] It is a compound of (W CCH2, CHR E , C=O, SO2, NH or N-alkyl, each X D It is selected independently from O, S, and H2. Y A CH2, -C=CR F , NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O or S, Z A X D and Z A Given that neither of them can be H2, they are O, S, or H2. G A and G B These are H and R, which are independent of each other. F Alkyl, OH, R are substituted in some cases. F OCOOR E , R F OCONR E R G , R F -CH2-heterocyclyl, which is sometimes substituted, and R F Selected from benzyl which may be substituted in some cases, Q A Q B Q C and Q D Each of them operates independently, CR F , N or N-oxide, A is H, alkyl, cycloalkyl, Cl, or F. R E -CONR F R G , -OR F , -NR F R G , -SR F , -SO2R F -SO2NR F R G ,-CR F R G ,-CR F NR F R Garyl, heteroaryl, optionally substituted alkyl, cycloalkyl, heterocycloalkyl, -P(O)(OR F )(R G ), -P(O)R F R G , -OP(O)(OR F )(R G ), -OP(O)R F R G , Haro, -CF3, -CN, -NR F SO2NR F R G , -NR F CONR F R G ,-CONR F COR G , -NR F C(=N-CN)NR F R G -C(=N-CN)NR F R G , -NR F C(=N-CN)R G , -NR F C(=C-NO2)NR F R G -SO2NR F COR G -NO2, -CO2R F , -C(C=N-OR F )R G ,-CR F =CR F R G , -CCR F -S(C=O)(C=NR F )R G -SF5 or -OCF3; R F and R G Each of these is independently a bond, H, N,N-oxide, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, or -C(O)R H Selected from, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl may be substituted, R H is hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, Z B (wherein is a functional group or atom, one of which may be modified to be covalently linked to the remainder of the compound of formula (I)). 【0149】 In some embodiments, Z B This is a combination that links ULM and WL in equation (I). 【0150】 In some embodiments, the ULM is a molar double microchromosome 2 homolog (MDM2), apoptosis protein 1 cell inhibitor (cIAP1), cereblon (CRBN), or von Hippel-Lindau (VHL). 【0151】 In some embodiments, the ULM is the portion that targets VHL ligase. 【0152】 In some embodiments, the ULM is the portion that targets cerebron ligase. 【0153】 In some embodiments, the ULM is a portion that targets a cell inhibitor of apoptosis protein 1 (cIAP1). 【0154】 In some embodiments, ULM 【0155】 [ka] (In the formula, R 40 is hydrogen or C 1~6 (It is alkyl.) Selected from. 【0156】 In some embodiments, R 40 It is hydrogen. 【0157】 In some embodiments, ULM 【0158】 [ka] The filename is TIFF0007872824000024.tif88161. 【0159】 Typical L part In some embodiments, L is a bond. 【0160】 In some embodiments, L is a connecting portion that is optionally replaced by B. 【0161】 In some embodiments, the connecting portion is alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkylene, heteroalkylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene. Each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkylylene, heteroalkylylene may optionally contain arylene, heteroarylene, cycloalkylene, or heterocycloalkylene. Furthermore, each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkylylene, heteroalkylylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene is oxo, halo, C 1~4 Alkyl, C 1~4 Alkoxy and C 1~4 It is independently and optionally substituted with 1 to 5 substituents independently selected from the haloalkyl group. 【0162】 In some embodiments, the connecting portion is formula -G1-((CH2) a -G2) c -(CH2) b -G3- (In the formula, Each of G1, G2, and G3 is independent, combined, -NR 28 -, -O-, -S(O) 0~2 -, -NR 28 C(O)-, -C(O)NR 28 -, -NR 28 S(O)2-, -S(O)2NR 28 -, -CR 29 =N-NR 28-, -NR 28 -N=CR 29 -, or -C(O)-, alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkylene, heteroalkylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene, and each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkylene, heteroalkylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene is oxo, halo, C 1~4 Alkyl, C 1~4 Alkoxy and C 1~4 They are independently and optionally substituted with 1 to 5 substituents independently selected from the haloalkyl group. Each R 28 These are, independently, hydrogen and C 1~4 Alkyl, C 1~4 It is a haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl. R 29 C 1~4 Alkyl, C 1~4 It is a haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl. a and b are independently 0, 1, 2, 3, 4, 5, 6, 7, or 8. c is an integer between 0 and 20. The connecting portion is on a replaceable atom, (-G4-(CH2) d -G5-) e -B It is replaced in some cases. G 4 and G 5 Each of them is independent, combined, -NR 28 -, -O-, -S(O) 0~2 -, -NR 28 C(O)-, -C(O)NR 28 -, -NR 28 S(O)2-, -S(O)2NR 28 -, -CR 29 =N-NR 28 -, -NR 28 -N=CR 29-, or -C(O)-, alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkylene, heteroalkylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene, and each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkylene, heteroalkylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene is oxo, halo, C 1~4 Alkyl, C 1~4 Alkoxy and C 1~4 They are independently and optionally substituted with 1 to 5 substituents independently selected from the haloalkyl group. (d and e are independently 0, 1, 2, 3, 4, 5, 6, 7, or 8.) It belongs to them. 【0163】 In some embodiments, the connecting portion is formula -G1-((CH2) a -G2) c -(CH2) b -G3- (In the formula, Each of G1, G2, and G3 is independent, combined, -NR 28 -, -O-, -S(O) 0~2 -, -NR 28 C(O)-, -C(O)NR 28 -, -NR 28 S(O)2-, -S(O)2NR 28 -, -CR 29 =N-NR 28 -, -NR 28 -N=CR 29 -, or -C(O)-, alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkylene, heteroalkylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene, and each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkylene, heteroalkylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene is oxo, halo, C 1~4 Alkyl, C 1~4 Alkoxy and C 1~4They are independently and optionally substituted with 1 to 5 substituents independently selected from the haloalkyl group. Each R 28 These are, independently, hydrogen and C 1~4 Alkyl, C 1~4 It is a haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl. R 29 C 1~4 Alkyl, C 1~4 It is a haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl. a and b are independently 0, 1, 2, 3, 4, 5, 6, 7, or 8. c is an integer between 0 and 20. It belongs to them. 【0164】 In some embodiments, the connecting portion is formula (-G1-(CH2) a -G2-(CH2) b -G3-) c (In the formula, Each of G1, G2, and G3 is independent, combined, -NR 28 -, -O-, -S(O) 0~2 -, -NR 28 C(O)-, -C(O)NR 28 -, -NR 28 S(O)2-, -S(O)2NR 28 -, -CR 29 =N-NR 28 -, -NR 28 -N=CR 29 -, or -C(O)-, alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkylene, heteroalkylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene, and each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkylene, heteroalkylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene is oxo, halo, C 1~4 Alkyl, C 1~4 Alkoxy and C 1~4They are independently and optionally substituted with 1 to 5 substituents independently selected from the haloalkyl group. Each R 28 Independently, C 1~4 Alkyl, C 1~4 It is a haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl. R 29 C 1~4 Alkyl, C 1~4 It is a haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl. a, b, and c are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8. The connecting portion is on a replaceable atom, (-G4-(CH2) d -G5-) e -B It is replaced in some cases. G 4 and G 5 Each of them is independent, combined, -NR 28 -, -O-, -S(O) 0~2 -, -NR 28 C(O)-, -C(O)NR 28 -, -NR 28 S(O)2-, -S(O)2NR 28 -, -CR 29 =N-NR 28 -, -NR 28 -N=CR 29 -, or -C(O)-, alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkylene, heteroalkylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene, and each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkylene, heteroalkylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene is oxo, halo, C 1~4 Alkyl, C 1~4 Alkoxy and C 1~4 They are independently and optionally substituted with 1 to 5 substituents independently selected from the haloalkyl group. (d and e are independently 0, 1, 2, 3, 4, 5, 6, 7, or 8.) It belongs to them. 【0165】 In some embodiments, the connecting portion is formula (-G1-(CH2) a -G2-(CH2) b -G3-) c (In the formula, Each of G1, G2, and G3 is independent, combined, -NR 28 -, -O-, -S(O) 0~2 -, -NR 28 C(O)-, -C(O)NR 28 -, -NR 28 S(O)2-, -S(O)2NR 28 -, -CR 29 =N-NR 28 -, -NR 28 -N=CR 29 -, or -C(O)-, alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkylene, heteroalkylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene, and each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkylene, heteroalkylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene is oxo, halo, C 1~4 Alkyl, C 1~4 Alkoxy and C 1~4 They are independently and optionally substituted with 1 to 5 substituents independently selected from the haloalkyl group. Each R 28 Independently, C 1~4 Alkyl, C 1~4 It is a haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl. R 29 C 1~4 Alkyl, C 1~4 It is a haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl. a, b, and c are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8. It belongs to them. 【0166】 In some embodiments, the connecting portion is formula 【0167】 [ka] (In the formula, the dashed lines represent the connection points to W and ULM, f is an integer between 1 and 20. Any substitutable atom may be further substituted with LB, where L is any linkage as described herein. It belongs to them. 【0168】 In some embodiments, the connecting portion is formula 【0169】 [ka] (In the formula, the dashed lines represent the connection points to W and ULM, f is an integer between 1 and 20. It belongs to them. 【0170】 Typical part B In some embodiments, L is a connecting portion that is optionally replaced by B, and B is the portion that crosses the blood-brain barrier. 【0171】 In some embodiments, the portion that crosses the blood-brain barrier is a molecule or macromolecule that can cross the blood-brain barrier by targeting receptors for transport across the blood-brain barrier. Such portions include those known in the art. 【0172】 In some embodiments, B is a carrier peptide, cholesterol, or a carrier peptide conjugated to cholesterol (by linkages or covalent bonds, as described herein, for example). 【0173】 In some embodiments, the carrier peptide is a peptide having approximately 5 to 35 residues and capable of passing through the cell membrane. Typical carrier peptides are known in the art. 【0174】 In some embodiments, B is Angiopep2, ApoE-I, ApoE-II, ApoB, THR, peptide-22, L57, TGN, leptin-30, RVG29, the Nipah virus envelope (env.) HR region conjugated to cholesterol, Newcastle disease virus conjugated to cholesterol, or measles virus peptide conjugated to cholesterol. 【0175】 Table 1 below shows the peptide sequences for representative B portions. 【0176】 [Table 1] 【0177】 Representative compounds In some embodiments, compounds selected from Table 2 or pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers thereof are provided. In some embodiments, compounds selected from Table 2 or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or isotope-enriched analogs thereof are provided. 【0178】 [Table 2] TIFF0007872824000029.tif239164TIFF0007872824000030.tif230164TIFF0007872824000031.tif241164 TIFF0007872824000032.tif234164TIFF0007872824000033.tif240164TIFF0007872824000034.tif214164 TIFF0007872824000035.tif228165TIFF0007872824000036.tif236166TIFF0007872824000037.tif255166 TIFF0007872824000038.tif225167TIFF0007872824000039.tif253168TIFF0007872824000040.tif205168 【0179】 Treatment method and use "Treatment" or "doing treatment" is a method for obtaining beneficial or desired outcomes, including clinical outcomes. Beneficial or desired clinical outcomes may include one or more of the following: a) preventing a disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and / or reducing the severity of the disease or condition); b) delaying or cessating the onset of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread of the disease or condition (e.g., metastasis)); and / or c) alleviating the disease, i.e., causing a reduction in clinical symptoms (e.g., improving the condition, achieving partial or complete remission of the disease or condition, enhancing the effects of other drug treatments, slowing the progression of the disease, increasing the quality of life, and / or extending survival). 【0180】 "Prevention" or "prevention" means any treatment of a disease or condition that prevents the clinical symptoms of the disease or condition from manifesting. In some embodiments, the compound may be administered to subjects (including humans) who are at risk of or have a family history of the disease or condition. 【0181】 "Subject" refers to an animal, such as a mammal (including humans), that has been or will be the subject of treatment, observation, or experimentation. The methods described herein may be useful in the treatment and / or veterinary use of humans. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human. 【0182】 In this specification, the terms “therapeutic effective dose” or “effective dose” for any compound or pharmaceutically acceptable salt thereof, stereoisomer, or mixture of stereoisomers described herein mean an amount sufficient to make the treatment effective when administered to a subject to produce a therapeutic benefit, such as improvement of symptoms or delay of disease progression. For example, a therapeutic effective dose may be an amount sufficient to reduce the symptoms of a disease or condition of hemodialysis (HD). The therapeutic effective dose may vary depending on the subject, the disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the mode of administration, and can be readily determined by those skilled in the art. 【0183】 The methods described herein can be applied to in vivo or ex vivo cell populations. “In vivo” means within a living organism, such as an animal or a human. In this context, the methods described herein can be used therapeutically in an organism. “Ex vivo” means outside a living organism. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including bodily fluid or tissue samples obtained from an organism. Such samples can be obtained by methods well known in the art. Typical biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used ex vivo to determine the optimal schedule and / or dosage of the compounds of the present invention for a given symptom, cell type, organism, and other parameters. Information gathered from such use can be used to establish protocols for in vivo treatments for experimental purposes or in a clinic setting. Other ex vivo uses to which the compounds and compositions described herein may be applicable are described below or will be apparent to those skilled in the art. The selected compounds may be further characterized to investigate their safety or tolerance in human or non-human subjects. Such properties can be investigated using methods generally known to those skilled in the art. 【0184】 In some embodiments, the compounds provided herein bind to a target protein, mHTT, and an E3 ubiquitin ligase complex. The formation of this ternary complex is intended to result in the transfer of multiple ubiquitin molecules to mHTT. Upon dissociation of the complex, the polyubiquitinated mHTT is recognized and degraded by the proteasome. 【0185】 Some embodiments provide a method for inducing the degradation of mHTT, comprising the step of administering a therapeutically effective amount of a compound or pharmaceutical composition described herein. 【0186】 In some embodiments, the degradation of mHTT provides a treatment for diseases caused by the aggregation of mHTT. 【0187】 The compounds disclosed herein are useful for the treatment of neurodegenerative diseases. 【0188】 In some embodiments, neurodegenerative diseases are caused by aggregates of mHTT. 【0189】 In some embodiments, the neurodegenerative disease is Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), or polyglutamine (polyQ) disease. 【0190】 In some embodiments, polyglutamine (polyQ) disease is dentatorubral-pallidoluysian atrophy (DRPLA), HD, spinal-bulbar muscular atrophy (ABMA), spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia type 3, spinocerebellar ataxia type 6, spinocerebellar ataxia type 7, or spinocerebellar ataxia type 17. 【0191】 Some embodiments provide a method for treating Huntington's disease, comprising the step of administering a therapeutically effective amount of a compound or pharmaceutical composition described herein. 【0192】 Combination therapy In some embodiments, the compounds disclosed herein may be used in combination with one or more additional therapeutic agents used and / or developed to treat neurodegenerative diseases. 【0193】 In some embodiments, the compounds disclosed herein may be used in combination with one or more additional therapeutic agents used and / or developed to treat HD. 【0194】 In some embodiments, one or more additional therapeutic agents may be compounds that activate the E3 enzyme, which would otherwise be downregulated by mHTT. 【0195】 In some embodiments, one or more additional therapeutic agents may be inhibitors to enhance cell uptake, such as p-glycoprotein 1 (pgp), or breast cancer resistance protein (BCRP) efflux inhibitors, such as elacridar. 【0196】 kit Kits comprising the compound of the present invention or a pharmaceutically acceptable salt thereof, stereoisomer, or mixture of stereoisomers, and suitable packaging are also provided herein. In some embodiments, the kit further includes instructions for use. In some embodiments, the kit includes the compound of the present invention or a pharmaceutically acceptable salt thereof, stereoisomer, or mixture of stereoisomers, and a label and / or instructions for the use of the compound in the treatment of symptoms, including diseases or conditions described herein. 【0197】 Products containing the compounds described herein or their pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers in a suitable container are also provided herein. The container may be a vial, bottle, ampoule, pre-filled syringe, or intravenous infusion bag. 【0198】 Pharmaceutical composition and mode of administration The compounds provided herein are typically administered in the form of pharmaceutical compositions. Therefore, pharmaceutical compositions containing one or more of the compounds described herein or their pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers, as well as one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and excipients, are also provided herein. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents containing sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. Such compositions are prepared by methods well known in the pharmaceutical field. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th edition (1985), and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd edition (edited by GS Banker and CT Rhodes). 【0199】 The pharmaceutical composition may be administered in single or multiple doses. The pharmaceutical composition may be administered by various methods, including, for example, rectally, orally, intranasally, and transdermally. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant. 【0200】 One mode of administration is parenteral, for example, by injection. Forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, sesame oil, corn oil, cottonseed oil or peanut oil and elixirs, aqueous or oil suspensions or emulsions having mannitol, dextrose or sterile aqueous solutions, and similar pharmaceutical vehicles. 【0201】 Oral administration may be another route of administration for the compounds described herein. Administration may be, for example, by capsule or enteric-coated tablet. In the preparation of pharmaceutical compositions comprising at least one compound described herein or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, the active ingredient is usually diluted with an excipient and / or encapsulated in a carrier which may be in the form of a capsule, sachet, paper or other container. Where the excipient acts as a diluent, the excipient may be in the form of a solid, semi-solid, or liquid material and act as a vehicle, carrier, or medium for the active ingredient. Thus, compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders. 【0202】 Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulation may further contain lubricants, such as talc, magnesium stearate, and mineral oil; humectants; emulsifiers and suspending agents; preservatives, such as methyl and propyl hydroxybenzoates; sweeteners; and flavorings. 【0203】 Compositions comprising at least one compound described herein or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof can be formulated to provide rapid, sustained-release, or delayed-release of the active ingredient after administration to a subject by employing procedures known in the art. Sustained-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled-release systems are shown in U.S. Patents 3,845,770, 4,326,525, 4,902,514 and 5,616,345. Another formulation for use in the methods disclosed herein employs a transdermal delivery device (patch). Such transdermal patches can be used to provide continuous or intermittent infusion of controlled amounts of the compounds described herein. The construction and use of transdermal patches for drug delivery are well known in the art. See, for example, U.S. Patents 5,023,252, 4,992,445, and 5,001,139. ​​Such patches can be constructed for continuous, pulsatile, or on-demand delivery of the drug. 【0204】 To prepare solid compositions, such as tablets, the main active ingredient can be mixed with pharmaceutical excipients to form a homogeneous solid preliminary formulation composition containing a compound described herein or a pharmaceutically acceptable salt thereof, stereoisomer, or mixture of stereoisomers. When these preliminary formulation compositions are referred to as homogeneous, the active ingredient can be uniformly dispersed throughout the composition so that the composition can be easily divided into equal effective unit dosage forms, such as tablets, pills, and capsules. 【0205】 Tablets or pills of the compounds described herein may be coated or otherwise formulated to provide a dosage form that offers the benefit of long-term action or to protect from the acidic conditions of the stomach. For example, tablets or pills may contain internal and externally administered components, the latter in the form of an outer coating covering the former. The two components may be separated by an enteric coating that helps withstand breakdown in the stomach and allows the internal component to pass through the duodenum intact or to be released with delay. A variety of materials may be used for such enteric coatings or coatings, and such materials include numerous polymer acids and mixtures of polymer acids with materials such as shellac, cetyl alcohol, and cellulose acetate. 【0206】 Compositions for inhalation or gas infusion may 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 herein. In some embodiments, compositions are administered orally or via the nasal respiratory route for topical or systemic effects. In other embodiments, compositions in pharmaceutically acceptable solvents may be sprayed using an inert gas. Sprayed 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. Compositions in solution, suspension, or powder form may be administered preferably orally or nasally from a device that delivers the formulation in an appropriate manner. 【0207】 Administration The specific dose level of the compounds of this application for any particular subject will depend on a variety of factors, including the activity of the specific compound employed, the age, weight, overall health, sex, diet, administration time, route of administration and elimination rate, drug combinations, and the severity of the particular disease. For example, the dosage can be expressed as the number of milligrams of the compound described herein per kilogram of the subject's body weight (mg / kg). Doses between approximately 0.1 and 150 mg / kg may be appropriate. In some embodiments, approximately 0.1 and 100 mg / kg may be appropriate. In other embodiments, dosages between 0.5 and 60 mg / kg may be appropriate. Normalization by subject weight is particularly useful when adjusting dosages across subjects of widely different sizes, for example, when using drugs in both children and adults, or when converting effective dosages in non-human subjects, such as dogs, to dosages suitable for human subjects. 【0208】 The daily dose may also be expressed as the total amount of the compounds described herein administered per dose or per day. The daily doses of the compounds described herein may be between approximately 1 mg and 4,000 mg, between approximately 2,000 and 4,000 mg / day, between approximately 1 and 2,000 mg / day, between approximately 1 and 1,000 mg / day, between approximately 10 and 500 mg / day, between approximately 20 and 500 mg / day, between approximately 50 and 300 mg / day, between approximately 75 and 200 mg / day, or between approximately 15 and 150 mg / day. 【0209】 When administered orally, the total daily dose for human subjects may range from 1 mg to 1,000 mg, between approximately 1,000 and 2,000 mg / day, between approximately 10 and 500 mg / day, between approximately 50 and 300 mg / day, between approximately 75 and 200 mg / day, or between approximately 100 and 150 mg / day. 【0210】 The compound or composition thereof of this application can be administered once, twice, three times, or four times a day using any preferred form as described above. Furthermore, administration or treatment with the compound can be continued for several days, for example, treatment can generally be continued for at least 7, 14, or 28 days per treatment cycle. 【0211】 Treatment cycles can be used, with rest periods of approximately 1 to 28 days, typically around 7 or 14 days, frequently alternating between cycles. In other embodiments, treatment cycles may be continuous. 【0212】 Compound Synthesis The compounds can be prepared using the methods disclosed herein, their customary modifications which would be apparent from the disclosure herein, and methods well known in the art. Conventional and well known synthetic methods can be used in addition to the teachings herein. The synthesis of typical compounds described herein can be achieved as described in the following examples. Reagents can be purchased, where available, from, for example, Sigma Aldrich or other chemical suppliers. 【0213】 general synthesis Typical embodiments of the compounds described herein can be synthesized using the general reaction scheme described below. As will be apparent from the descriptions herein, the general scheme can be modified by substituting the starting materials with other materials having similar structures, thereby yielding different products. To provide numerous examples of how the starting materials can be varied to yield the corresponding products, the synthesis is described thereafter. Given the desired product with defined substituents, the required starting materials can generally be determined by inspection. The starting materials are typically obtained from commercial sources or synthesized using publicly available methods. To synthesize the compounds that are embodiments described herein, inspection of the structure of the compound to be synthesized will provide the identity of each substituent. As will be apparent from the examples herein, the identity of the required starting materials will generally become clear from the identity of the final product through a simple inspection process. Generally, the compounds described herein are typically stable and isolated at room temperature and room pressure. 【0214】 The compound of formula (I) can be synthesized by the following typical synthetic routes. 【0215】 [ka] 【0216】 In Scheme 1, PG refers to a protecting group, and W, L, and ULM are as defined herein. As shown in Scheme 1, in some embodiments, compounds 1-1 and 1-2 are coupled under suitable conditions (e.g., by the Mitsunobu reaction) to form compound 1-3. Compound 1-4 is obtained by suitable deprotection of compound 1-3. Compounds of formula (I) are produced from the coupling of compound 1-4 with ULM (e.g., in the presence of HATU and a base). 【0217】 [ka] 【0218】 In Scheme 2, LG refers to a leaving group, and W, L, and ULM are as defined herein. As shown in Scheme 2, in some embodiments, compounds 2-1 and 2-2 are coupled under appropriate conditions (e.g., in the presence of a base) to form compound 2-3. Compounds of formula (I) are produced from the coupling of compound 2-3 with W (e.g., in the presence of a base). 【0219】 [ka] 【0220】 In scheme 3, L A and L B L is as described herein independently, and W, ULM, and B are as described herein. As shown in Scheme 3, in some embodiments, the compound of formula (I)(i) is coupled to compound 3-1 and compound 3-2 under standard coupling conditions (e.g., azide substitution of compound 3-1 L). A and 3-2 alkynyl substitution L B This can be achieved by coupling (through a click chemical reaction between them). [Examples] 【0221】 The following embodiments are included to represent specific embodiments of the present invention. Those skilled in the art will understand that the techniques disclosed in the following embodiments represent techniques for working well in the practice of the present invention and can therefore be considered to constitute a particular mode of that practice. However, those skilled in the art will understand that numerous modifications can be made in light of the present invention to the specific embodiments disclosed, and similar or analogous results can still be obtained without departing from the spirit and scope of the present invention. 【0222】 General synthesis procedure. Commercially available reagents and solvents (HPLC grade) were used without further purification. 1 ¹H NMR spectra were recorded in a deuterated solvent using a Bruker DRX 500 MHz spectrometer or a Bruker DPX 250 MHz spectrometer. Chemical shifts (δ) are expressed in parts per million. Thin-layer chromatography (TLC) analysis was performed using a Kieselgel 60 F 254 The procedure was performed using a (Merck) plate and visualized using UV light. 【0223】 Analytical HPLC-MS was performed on a Shimadzu LCMS-2010EV system using a reversed-phase Atlantis dC18 column (3 μm, 2.1 × 50 mm), a gradient of 5–100% B over 3 minutes (A = water / 0.1% formic acid, B = acetonitrile / 0.1% formic acid), an injection volume of 3 μL, and a flow rate of 1.0 mL / min. UV spectra were recorded at 215 nm using a Waters 2788 dual-wavelength UV detector. Mass spectra were obtained over the m / z range of 150–850 using analytical HPLC-MS on a Shimadzu LCMS-2010EV system with a sampling rate of 2 scans per second, using a Waters LCT or reversed-phase Waters Atlantis dC18 column (3 μm, 2.1 × 100 mm), a gradient of 5–100% B (A = water / 0.1% formic acid, B = acetonitrile / 0.1% formic acid) over 7 minutes, an injection volume of 3 μl, and a flow rate of 0.6 mL / min. UV spectra were recorded at 215 nm using a Waters 2996 photodiode array. Data were integrated and recorded using Shimadzu Psiport software. 【0224】 Alternatively, the following was used: Proton nuclear magnetic resonance spectra were obtained at 500 MHz using a Bruker ASCEND 500 spectrometer. Spectra were shown in ppm(δ), and coupling constants and J values ​​were recorded in Hertz (Hz). Tetramethylsilane was used as an internal standard for proton nuclear magnetic resonance. Mass spectra and LCMS analyses were obtained using a Varian 1200L single quadrupole mass spectrometer (ESI, HP-LCMS), Waters Acquity SQD (ESI, UP-LCMS), or Shimadzu 2020 single quadrupole mass spectrometer (DUIS, UP-LCMS). HPLC analyses were obtained using either a Phenomenex Luna C18(2) column, 5 μm, (4.6 × 150 mm) with elution by solvent gradient method 1, or a Phenomenex C18 Kinetex column, 5 μm (4.6 × 150 mm) with elution by solvent gradient method 2. Detection was performed using UV absorbance at 254 nm. 【0225】 [Table 3] 【0226】 [Table 4] 【0227】 Abbreviation Acetic acid (ACOH) aq - water-based Boc-tert-butyloxycarbonyl CMBP - Cyanomethyltributylphosphoran DCM - Dichloromethane DIAD - Diisopropyl azodicarboxylate DIPEA - Diisopropylethylamine DMF - N,N-dimethylformamide DMSO - Dimethyl sulfoxide EDC - N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide ESI - Electrospray Ionization Et-ethyl HCl - ethyl acetate EtOH - Ethanol FCC - Flash Column Chromatography h - time HATU - 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HOBT-hydroxybenzotriazole HPLC - High-Performance Liquid Chromatography IPA - Isopropanol LCMS - Liquid Chromatography Mass Spectrometry Me - Methyl MeCN - Acetonitrile MeOH - methanol minutes - minutes Ms-methylsulfonyl m / z - mass-to-charge ratio NMR - nuclear magnetic resonance O / N - All Night Ph - Phenylen ppm - parts per million rt- room temperature sat. - saturation TBME - tert-butylmethyl ether tBu - tert-butyl TFA - Trifluoroacetic acid THF - Tetrahydrofuran TLC - Thin-Layer Chromatography Ts-p-toluenesulfonyl UV - ultraviolet light 【0228】 [Synthesis Examples] [Example 1] Scheme for Example 1 【0229】 [ka] 【0230】 Step 1: Methyl 5-(2-{2-[2-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)ethoxy]ethoxy}ethoxy)pyridine-2-carboxylate A stirred solution of methyl 5-hydroxypyridine-2-carboxylate (100 mg, 0.65 mmol) and tert-butyl N-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethyl)carbamate (211 mg, 0.72 mmol) in THF (7.5 mL) was cooled to 0°C and treated with triphenylphosphine (257 mg, 0.98 mmol). The reaction mixture was stirred for 5 minutes, and then treated with the dropwise addition of a solution of DIAD (192 μL, 0.98 mmol) in THF (2.5 mL) for 5 minutes. The mixture was stirred at 0°C for a further 10 minutes, then at room temperature overnight. The reaction mixture was concentrated to reduce its volume, then diluted with water (20 mL) and extracted with DCM (4 × 20 mL). The combined organic extract was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under vacuum. The crude material was purified by acid reverse-phase chromatography (C-18, 0-100% MeCN / water + 0.1% formic acid) to obtain the title compound. 1 H NMR (250 MHz, chloroform-d) δ 8.40 (d, J = 2.8 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.37 - 7.21 (m, 1H), 5.00 (d, J = 6.3 Hz, 1H), 4.23 (dd, J = 5.7, 3.7 Hz, 2H), 3.95 (s, 3H), 3.90 - 3.83 (m, 2H), 3.78 - 3.56 (m,8H), 3.51 (t, J = 5.2 Hz, 2H), 3.27 (q, J = 5.4 Hz, 2H), 1.41 (s, 9H). Tr(METCR1410) = 1.03 minutes, (ES + ) [M+H] + 429. 【0231】 Step 2: Methyl 5-(2-{2-[2-(2-azaniumylethoxy)ethoxy]ethoxy}ethoxy)pyridine-2-carboxylate chloride A mixture of methyl 5-(2-{2-[2-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)ethoxy]ethoxy}ethoxy)pyridine-2-carboxylate (170 mg, 0.38 mmol) in 4N HCl in dioxane (4 mL) was stirred at room temperature for 3 hours. The reaction mixture was then evaporated to dryness to obtain the title compound. 1 H NMR (500 MHz, methanol-d4) δ 8.58 (d, J = 2.8 Hz, 1H), 8.39 (d, J = 8.9 Hz, 1H), 8.06 (dd, J = 8.9, 2.8 Hz, 1H), 4.48 - 4.42 (m, 2H), 4.05 (s, 3H), 3.98 - 3.88 (m, 2H), 3.76 - 3.67 (m, 10H), 3.13 (t, J = 5.1 Hz, 2H). Tr(METCR1410) = 0.71 min, (ES + ) [M+H] + 329. 【0232】 Step 3: Methyl 5-{2-[2-(2-{2-[(2S)-2-[(2S,3R)-3-{[(tert-butoxy)carbonyl]amino}-2-hydroxy-4-phenylbutanamide]-4-methylpentanamide]ethoxy}ethoxy)ethoxy]ethoxy}pyridine-2-carboxylate DIPEA (407 μL, 2.34 mmol) was added dropwise to a suspension of methyl 5-(2-{2-[2-(2-azaniumylethoxy)ethoxy]ethoxy}ethoxy)pyridine-2-carboxylate chloride (138 mg, 0.36 mmol), (2S)-2-[[(2S,3R)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenyl-butanoyl]amino]-4-methylpentanoic acid (160 mg, 0.36 mmol), HOBT (124 mg, 0.81 mmol), and EDC.HCl (276 mg, 1.44 mmol), cooled to 0°C, and the mixture was cooled to 0°C. The mixture was stirred at 0°C for 15 minutes and then warmed to room temperature overnight. The reaction product was concentrated to dryness, and the crude oily substance was partitioned between water and ethyl acetate. The aqueous layer was extracted once more, and then the combined extract was washed with 10% citric acid (aq), saturated NaHCO3 (aq), and brine. The organic layer was dried over MgSO4, filtered, and evaporated to dryness to obtain the title compound. 1H NMR (500 MHz, chloroform-d) δ 8.45 (d, J = 2.9 Hz, 1H), 8.14 (d, J = 8.7 Hz, 1H), 7.41 (d, J = 8.7 Hz, 1H), 7.34 (dd, J = 8.7, 2.9 Hz, 1H), 7.32 - 7.28 (m, 3H), 7.25 - 7.21 (m, 2H), 6.82 (t, J = 5.6 Hz, 1H), 5.69 (s, 1H), 5.16 (d, J = 8.5 Hz, 1H), 4.51 (td, J = 9.1, 5.0 Hz, 1H), 4.32 - 4.27 (m, 2H), 4.19 - 4.16 (m, 1H), 4.11 (d, J = 8.2 Hz, 1H), 4.01 (s, 3H), 3.97 - 3.93 (m, 2H), 3.81 - 3.75 (m, 2H), 3.73 - 3.68 (m, 2H), 3.66 - 3.59 (m, 4H), 3.56 (t, J = 5.4 Hz, 2H), 3.48 - 3.40 (m, 2H), 3.11 - 3.02 (m, 2H), 1.79 - 1.57 (m, 3H), 1.42 (s, 9H), 0.96 (d, J = 6.2 Hz, 3H), 0.94 (d, J = 6.2 Hz, 3H). Tr(METCR1410) = 1.11 minutes, (ES + ) [M+H] + 719. 【0233】 Step 4: 5-{2-[2-(2-{2-[(2S)-2-[(2S,3R)-3-{[(tert-butoxy)carbonyl]amino}-2-hydroxy-4-phenylbutanamide]-4-methylpentanamide]ethoxy}ethoxy)ethoxy]ethoxy}pyridine-2-carboxylic acid A solution of methyl 5-{2-[2-(2-{2-[(2S)-2-[(2S,3R)-3-{[(tert-butoxy)carbonyl]amino}-2-hydroxy-4-phenylbutanamide]-4-methylpentanamide]ethoxy}ethoxy)ethoxy]ethoxy}pyridine-2-carboxylate (250 mg, 0.35 mmol) and K2CO3 (144 mg, 1.04 mmol) in a 2:1 MeOH:water mixture (7.5 mL) was stirred at room temperature for 24 hours. The mixture was concentrated to reduce its volume and then acidified to pH 4 / 5 with a 10% citric acid solution. The aqueous phase was extracted with DCM (4 × 15 mL), the combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated to dryness to obtain the title compound. 1 H NMR (250 MHz, chloroform-d) δ 8.32 (d, J = 2.8 Hz, 1H), 8.15 (d, J = 8.7 Hz, 1H), 7.40 (dd, J = 8.7, 2.8 Hz, 1H), 7.24 (d, J = 8.8 Hz, 5H), 6.86 - 6.72 (m, 1H), 5.08 (s, 1H), 4.59 - 4.40 (m, 1H), 4.28 (dd, J = 5.6, 3.6 Hz, 2H), 4.15 (d, J = 2.6 Hz, 3H), 3.99 - 3.84 (m, 2H), 3.81 - 3.34 (m, 10H), 2.95 (s, 2H), 1.80 - 1.52 (m, 3H), 1.37 (s, 9H), 0.90 (t, J = 6.4 Hz, 6H). Tr(METCR1410) = 1.10 min, (ES + ) [M+H] + 705. 【0234】 Step 5: tert-butyl N-[(1S,2R)-1-hydroxy-1-{[(1S)-3-methyl-1-({2-[2-(2-{2-[(6-{[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]carbamoyl}pyridine-3-yl)oxy]ethoxy}ethoxy)ethoxy]ethyl}carbamoyl)butyl]carbamoyl}-3-phenylpropane-2-yl]carbamate HATU (71 mg, 0.19 mmol) was added to a solution of DIPEA (82 μL, 0.47 mmol), 5-{2-[2-(2-{2-[(2S)-2-[(2S,3R)-3-{[(tert-butoxy)carbonyl]amino}-2-hydroxy-4-phenylbutanamide]-4-methylpentanamide]ethoxy}ethoxy)ethoxy]ethoxy}pyridine-2-carboxylic acid (110 mg, 0.16 mmol), and 2-(pyridine-3-yl)-1,3-benzoxazole-5-amine (33 mg, 0.16 mmol) in THF (2 mL) cooled to 0°C. After 1.5 hours, the reaction mixture was evaporated to dryness and then partitioned between ethyl acetate and 10% citric acid. The organic layer was washed with saturated NaHCO3(aq)(2×), dried over Na2SO4, filtered, and evaporated to dryness to obtain the title compound. 1 H NMR (250 MHz, chloroform-d) δ 9.97 (s, 1H), 9.48 - 9.38 (m, 1H), 8.74 (dd, J = 4.9, 1.7 Hz, 1H), 8.49 (dt, J = 8.1, 1.9 Hz, 1H), 8.32 - 8.18 (m, 3H), 7.74 (dd, J = 8.8, 2.1 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.45 (dd, J = 8.0, 4.8 Hz, 1H), 7.36 (dd, J = 8.7, 2.9 Hz, 2H), 7.25 - 7.12 (m, 5H), 6.91 - 6.79 (m, 1H), 5.72 (s, 1H), 5.19 (d, J = 8.5 Hz, 1H), 4.46 (td, J = 8.8, 3.4 Hz, 1H), 4.25 (dd, J = 5.7, 3.5 Hz, 2H), 4.15 - 4.04 (m, 2H), 3.89 (dd, J = 5.6, 3.5 Hz, 2H), 3.76 - 3.48 (m, 10H), 3.38 (q, J = 5.2 Hz, 2H), 3.03 - 2.92 (m, 2H), 1.71 - 1.54 (m, 3H), 1.34 (s, 9H), 0.98 - 0.83 (m, 6H). Tr(METCR1603) = 4.81 minutes, (ES) +[M+H] + 899. 【0235】 Step 6: 5-{2-[2-(2-{2-[(2S)-2-[(2S,3R)-3-azaniumyl-2-hydroxy-4-phenylbutanamide]-4-methylpentanamide]ethoxy}ethoxy)ethoxy]ethoxy}-N-[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]pyridine-2-carboxamide diformate 4N HCl in dioxane (2.0 mL, 8.00 mmol) was added to a solution of tert-butyl N-[(1S,2R)-1-hydroxy-1-{[(1S)-3-methyl-1-({2-[2-(2-{2-[(6-{[2-(pyridine-3-yl)-1,3-benzoxazole-5-yl]carbamoyl}pyridine-3-yl)oxy]ethoxy}ethoxy)ethoxy]ethyl}carbamoyl)butyl]carbamoyl}-3-phenylpropane-2-yl]carbamate (138 mg, 0.15 mmol) in MeOH (1 mL). The reaction mixture was stirred at room temperature for 1 hour, then evaporated to dryness. The crude product was dissolved in water and extracted with Et2O. The aqueous layer was neutralized with solid NaHCO3, and then extracted with ELISA (3 × 20 mL). The combined toluene extracts were washed with brine, dried over MgSO4, filtered, and evaporated to dryness. The crude residue was purified by acid reverse-phase chromatography (C-18, 0-100% MeCN / water + 0.1% formic acid) to obtain the title compound. 1H NMR (500 MHz, メタノール-d4) δ 9.38 (d, J = 2.1 Hz, 1H), 8.75 (dd, J = 4.9, 1.6 Hz, 1H), 8.62 (dt, J = 8.1, 1.9 Hz, 1H), 8.39 (d, J = 2.8 Hz, 1H), 8.37 (d, J = 2.0 Hz, 1H), 8.29 (s, 2H), 8.18 (d, J = 8.7 Hz, 1H), 7.76 (dd, J = 8.8, 2.1 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.66 (dd, J = 8.0, 4.9 Hz, 1H), 7.57 (dd, J = 8.7, 2.9 Hz, 1H), 7.37 - 7.26 (m, 5H), 4.38 (dd, J = 8.6, 6.3 Hz, 1H), 4.35 - 4.27 (m, 2H), 4.12 (d, J = 3.1 Hz, 1H), 3.94 - 3.85 (m, 2H), 3.76 (td, J = 7.5, 3.1 Hz, 1H), 3.73 - 3.70 (m, 2H), 3.68 - 3.65 (m, 2H), 3.64 - 3.61 (m, 2H), 3.59 - 3.56 (m, 2H), 3.52 (t, J = 5.5 Hz, 2H), 3.44 - 3.34 (m, 1H), 3.35 - 3.29 (m, 1H), 3.10 (dd, J = 13.9, 7.9 Hz, 1H), 2.91 (dd, J = 13.9, 7.1 Hz, 1H), 1.73 - 1.56 (m, 3H), 0.99 - 0.92 (m, 6H). Tr(MET-uPLC-AB-101) = 2.31 points, (ES + [M+H] + 798. 【0236】 The following compounds are the same as those mentioned above. 【0237】 Table 5 TIFF0007872824000048.tif142167 【0238】 [Example 2] Scheme for Example 2 【0239】 [ka] 【0240】 Step 1: 5-Hydroxy-N-[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazole-5-yl]pyridine-2-carboxamide 6-(5-amino-1,3-benzoxazole-2-yl)-2-methylpyridazine-3-one (200 mg, 0.83 mmol) and 5-hydroxypyridine-2-carboxylic acid (115 mg, 0.83 mmol) were combined in DMF (5 mL) and cooled to 0°C. N-ethyl-N-(propan-2-yl)propan-2-amine (160 μL, 0.91 mmol) was added, followed by HATU (380 mg, 0.99 mmol). The reaction mixture was heated overnight at room temperature. Water was slowly added to induce precipitation. The resulting precipitate was separated using filter paper and dried under vacuum to obtain the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 2.7 Hz, 1H), 8.19 (d, J = 9.7 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.97 (dd, J = 8.9, 2.0 Hz, 1H), 7.81 (d, J = 8.9 Hz, 1H), 7.38 (dd, J = 8.6, 2.7 Hz, 1H), 7.15 (d, J = 9.7 Hz, 1H), 3.82 (s, 3H). 【0241】 Step 2: tert-butyl 2-{2-[(6-{[2-(1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)-1,3-benzoxazole-5-yl]carbamoyl}pyridine-3-yl)oxy]ethoxy}acetate 5-Hydroxy-N-[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazole-5-yl]pyridine-2-carboxamide (282 mg, 0.78 mmol) and tert-butyl 2-(2-hydroxyethoxy)acetate (140 mg, 0.78 mmol) were suspended in THF (10 mL). Triphenylphosphine (300 mg, 1.16 mmol) was added all at once, and the suspension was stirred for 10 minutes. Then, DIAD (230 μl, 1.16 mmol) was added, and the suspension was stirred overnight. The solid was separated using filter paper to obtain the title compound. 1 H NMR (250 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.49 - 8.41 (m, 2H), 8.22 - 8.14 (m, 2H), 8.00 (dd, J = 9.0, 2.1 Hz, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.66 (dd, J = 8.7, 2.9 Hz, 1H), 7.15 (d, J = 9.7 Hz, 1H), 4.33 (d, J = 4.5 Hz, 2H), 4.09 (s, 2H), 3.88 (s, 2H), 3.82 (s, 3H), 1.44 (s, 8H). 【0242】 Step 3: 2-{2-[(6-{[2-(1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)-1,3-benzoxazole-5-yl]carbamoyl}pyridine-3-yl)oxy]ethoxy}acetic acid 150 mg, 0.29 mmol of tert-butyl 2-{2-[(6-{[2-(1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)-1,3-benzoxazole-5-yl]carbamoyl}pyridine-3-yl)oxy]ethoxy}acetate was suspended in THF:water (5 mL:2 mL). 80 mg, 0.58 mmol of K2CO3 was added, and the reaction mixture was rapidly stirred overnight at room temperature. No conversion to the desired product was observed. The reaction mixture was concentrated and suspended in DCM (10 mL). 2 mL of TFA was added, and the reaction mixture was stirred overnight. The reaction mixture was concentrated and then directly purified by acidic prep-HPLC to obtain the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.45 (dd, J = 14.4, 2.4 Hz, 2H), 8.18 (dd, J = 15.4, 9.2 Hz, 2H), 8.00 (dd, J = 8.9, 2.1 Hz, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.66 (dd, J = 8.8, 2.9 Hz, 1H), 7.16 (d, J = 9.7 Hz, 1H), 4.39 - 4.30 (m, 2H), 4.11 (s, 2H), 3.89 (dd, J = 5.2, 3.6 Hz, 2H), 3.82 (s, 3H). 【0243】 Step 4: 5-[2-({[(2R)-1-[(2R,4S)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazole-5-yl)phenyl]methyl}carbamoyl)pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methoxy)ethoxy]-N-[2-(1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)-1,3-benzoxazole-5-yl]pyridine-2-carboxamide (Compound 51) (2R,4S)-1-[(2R)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazole-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (11 mg, 0.03 mmol) and 2-{2-[(6-{[2-(1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)-1,3-benzoxazole-5-yl]carbamoyl}pyridine-3-yl)oxy]ethoxy}acetic acid (12 mg, 0.03 mmol) were combined in DMF (1 mL). DIPEA (15 μL, 0.08 mmol) was added, followed by HATU (12 mg, 0.03 mmol). The reaction mixture was stirred overnight, and then directly purified by basic prep-HPLC to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.94 (s, 1H), 8.59 (t, J = 6.0 Hz, 1H), 8.50 (d, J = 2.9 Hz, 1H), 8.41 (d, J = 2.0 Hz, 1H), 8.19 - 8.15 (m, 1H), 8.13 (d, J = 8.7 Hz, 1H), 7.93 (dd, J = 8.9, 2.1 Hz, 1H), 7.79 (d, J = 8.9 Hz, 1H), 7.70 (dd, J = 8.8, 2.8 Hz, 1H), 7.53 (d, J = 9.6 Hz, 1H), 7.42 (d, J = 8.3 Hz, 2H), 7.39 - 7.35 (m, 2H), 7.14 (d, J = 9.7 Hz, 1H), 5.17 (d, J = 3.5 Hz, 1H), 4.62 (d, J = 9.6 Hz, 1H), 4.51 - 4.26 (m, 6H), 4.09 (s, 2H), 3.92 (t, J = 4.4 Hz, 2H), 3.81 (s, 3H), 3.70 (dd, J = 10.6, 4.0 Hz, 1H), 3.62 (d, J = 10.8 Hz, 1H), 2.40 (s, 3H), 2.12 - 2.04 (m, 1H), 1.92 (ddd, J = 13.0, 8.8, 4.5 Hz, 1H), 0.96 (d, J = 9.4 Hz, 9H). Tr(METCR1603 high pH 7) = 3.82, (ES + (M+H) + 878. 【0244】 [Example 3] Example 3 【0245】 【change】 【0246】 Step 1: tert-butyl N-{2-[2-(2-{[6-({[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazole-5-yl]oxy}methyl)pyridine-3-yl]oxy}ethoxy)ethoxy]ethyl}carbamate DIAD (68 μL, 0.344 mmol) was added to a solution of tert-butyl N-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}carbamate (57 mg, 0.229 mmol), 6-{5-[(5-hydroxypyridine-2-yl)methoxy]-1,3-benzoxazole-2-yl}-2-methyl-2,3-dihydropyridazine-3-one (110 mg, 0.229 mmol), and Ph3P (90 mg, 0.344 mmol) in DMF (0.8 mL). The resulting mixture was stirred at room temperature for 36 hours, then evaporated to dryness, adsorbed onto silica, and purified by FCC (silica, 0-10% MeOH in DCM) to obtain the title compound. 1 H NMR (500 MHz, chloroform-d) δ 8.34 (d, J = 2.8 Hz, 1H), 8.11 (d, J = 9.7 Hz, 1H), 7.49 - 7.41 (m, 2H), 7.33 (d, J = 2.5 Hz, 1H), 7.29 - 7.26 (m, 1H), 7.11 (dd, J = 9.0, 2.5 Hz, 1H), 7.06 (d, J = 9.7 Hz, 1H), 5.20 (s, 2H), 5.03 (s, 1H), 4.19 (dd, J = 5.6, 3.9 Hz, 2H), 3.94 (s, 3H), 3.89 - 3.83 (m, 2H), 3.77 - 3.50 (m, 6H), 3.31 (q, J = 5.7 Hz, 2H), 1.42 (s, 9H). Tr(METCR1603) = 4.13 min, (ES) + [M+H] + 582. 【0247】 Step 2: 6-{5-[(5-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}pyridine-2-yl)methoxy]-1,3-benzoxazole-2-yl}2-methyl-2,3-dihydropyridazine-3-one HCl (4N in dioxane, 1.50 mL, 6.00 mmol) was added to a solution of tert-butyl N-{2-[2-(2-{[6-({[2-(1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)-1,3-benzoxazole-5-yl]oxy}methyl)pyridine-3-yl]oxy}ethoxy)ethoxy]ethyl}carbamate (19%, 256 mg, 0.084 mmol) in MeOH (0.5 mL). The mixture was stirred at room temperature for 2 hours, then partitioned between DCM and 2N HCl (aq). The organic layer was extracted once more with 2N HCl. The combined aqueous layer was neutralized with Na2CO3, then extracted with DCM (3×). The combined organic layer was dried over MgSO4, filtered, and evaporated to dryness to obtain the title compound. 1 H NMR (250 MHz, chloroform-d) δ 8.34 (d, J = 2.9 Hz, 1H), 8.11 (d, J = 9.7 Hz, 1H), 7.52 (d, J = 9.0 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.31 - 7.24 (m, 1H), 7.12 (dd, J = 9.0, 2.5 Hz, 1H), 7.06 (d, J = 9.7 Hz, 1H), 5.20 (s, 2H), 4.27 - 4.15 (m, 2H), 3.95 (s, 3H), 3.88 (dd, J = 5.6, 3.8 Hz, 2H), 3.79 - 3.50 (m, 6H), 2.94 - 2.83 (m, 2H). Tr(METCR1410) = 0.90 min, (ES) + [M+H] + 482. 【0248】 Step 3: (2S)-4-methyl-N-{2-[2-(2-{[6-({[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazole-5-yl]oxy}methyl)pyridine-3-yl]oxy}ethoxy)ethoxy]ethyl}-2-(4-phenylbutanamide)pentanamide (compound 52) DIPEA (61 μL, 0.351 mmol) was added to a solution of 6-{5-[(5-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}pyridine-2-yl)methoxy]-1,3-benzoxazole-2-yl}-2-methyl-2,3-dihydropyridazine-3-one (65%, 40 mg, 0.054 mmol), N-(4-phenylbutanoyl)-L-leucine (15 mg, 0.054 mmol), EDC.HCl (41 mg, 0.216 mmol), and HOBT (19 mg, 0.121 mmol), cooled to 0°C. The reaction mixture was stirred at room temperature while monitoring by LC-MS. After 7 hours, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with 10% citric acid solution (aq), saturated NaHCO3 (aq), and brine. The organic phase was dried over MgSO4, filtered, and evaporated to dryness. The resulting residue was purified by acidic prep HPLC to obtain the title compound. 1H NMR (500 MHz, メタノール-d4) δ 8.28 (d, J = 2.8 Hz, 1H), 8.21 (d, J = 9.7 Hz, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.47 (dd, J = 8.6, 2.9 Hz, 1H), 7.37 (d, J = 2.5 Hz, 1H), 7.27 - 7.09 (m, 7H), 5.19 (s, 2H), 4.38 (t, J = 7.6 Hz, 1H), 4.25 - 4.20 (m, 2H), 3.91 (s, 3H), 3.86 - 3.82 (m, 2H), 3.70 - 3.65 (m, 2H), 3.64 - 3.57 (m, 2H), 3.52 (t, J = 5.5 Hz, 2H), 3.40 - 3.32 (m, 2H), 2.63 - 2.53 (m, 2H), 2.24 (t, J = 7.5 Hz, 2H), 1.96 - 1.83 (m, 2H), 1.64 (dp, J = 13.3, 6.6 Hz, 1H), 1.54 (dd, J = 8.0, 6.6 Hz, 2H), 0.93 (d, J = 6.6 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H). Tr(METCR1603) = 4.41 points, (ES) + [M+H] + 741. 【0249】 [Example 4] Example 4 【0250】 【change】 【0251】 Step 1: (2S)-4-methyl-N-{2-[2-(2-{[6-({[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazole-5-yl]oxy}methyl)pyridine-3-yl]oxy}ethoxy)ethoxy]ethyl}-2-(4-phenylbutanamide)pentanamide DIPEA (61 μL, 0.350 mmol) was added to a solution of 6-{5-[(5-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}pyridine-2-yl)methoxy]-1,3-benzoxazole-2-yl}-2-methyl-2,3-dihydropyridazine-3-one (74%, 35 mg, 0.054 mmol), (2S)-2-[[(2S,3R)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenyl-butanoyl]amino]-4-methylpentanoic acid (23 mg, 0.054 mmol), EDC.HCl (41 mg, 0.215 mmol), and HOBT (19 mg, 0.121 mmol), which had been cooled to 0°C. The solution was then heated to room temperature for 18 hours. After this, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with 10% citric acid solution (aq), saturated NaHCO3 (aq), and brine, then dried over MgSO4, filtered, and evaporated to dryness. The crude residue was purified by acidic prep HPLC to obtain the title compound. 11H NMR (500 MHz, chloroform-d) δ 8.37 (d, J = 2.8 Hz, 1H), 8.09 (d, J = 9.7 Hz, 1H), 7.52 (d, J = 8.9 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.33 - 7.16 (m, 8H), 7.10 (dd, J = 8.9, 2.5 Hz, 1H), 7.05 (d, J = 9.7 Hz, 1H), 6.83 (s, 1H), 5.84 (s, 1H), 5.38 (d, J = 8.1 Hz, 1H), 5.16 (d, J = 12.7 Hz, 1H), 5.12 (d, J = 12.7 Hz, 1H), 4.45 (td, J = 9.0, 5.2 Hz, 1H), 4.28 - 4.16 (m, 2H), 4.13 (d, J = 2.6 Hz, 1H), 4.03 (d, J = 8.3 Hz, 1H), 3.95 (s, 3H), 3.85 (ddt, J = 5.0, 4.0, 1.8 Hz, 2H), 3.68 (dd, J = 5.2, 3.9 Hz, 2H), 3.65 - 3.58 (m, 2H), 3.54 (t, J = 5.2 Hz, 2H), 3.41 (t, J = 5.4 Hz, 2H), 3.16 - 3.07 (m, 1H), 3.01 - 2.94 (m, 1H), 1.72 - 1.53 (m, 3H), 1.36 (s, 9H), 0.90 (d, J = 6.2 Hz, 3H), 0.86 (d, J = 6.2 Hz, 3H). Tr(MET-uHPLC-AB-101) = 3.52 min, (ES) + [M+H] + 872. 【0252】 Step 2: (2S)-2-[(2S,3R)-3-azaniumyl-2-hydroxy-4-phenylbutanamide]-4-methyl-N-{2-[2-(2-{[6-({[2-(1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)-1,3-benzoxazole-5-yl]oxy}methyl)pyridine-3-yl]oxy}ethoxy)ethoxy]ethyl}pentanamide formate (compound 49) HCl (4N in dioxane, 200 μL, 0.800 mmol) was added dropwise to a solution of (2S)-4-methyl-N-{2-[2-(2-{[6-({[2-(1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)-1,3-benzoxazole-5-yl]oxy}methyl)pyridine-3-yl]oxy}ethoxy)ethoxy]ethyl}-2-(4-phenylbutanamide)pentanamide (12 mg, 0.014 mmol) in MeOH (0.15 mL) stirred at room temperature. After 3.5 hours, the reaction was evaporated to dryness, and the residue was partitioned between HCl and saturated NaHCO3 (aq). The aqueous layer was extracted twice with HCl. The combined organic layers were dried over MgSO4, filtered, and evaporated to dryness. The crude product was purified by acidic prep HPLC to obtain the title compound. 1H NMR (500 MHz, methanol-d4) δ 8.43 (s, 1H), 8.29 (d, J = 2.8 Hz, 1H), 8.19 (d, J = 9.7 Hz, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.47 (dd, J = 8.6, 2.9 Hz, 1H), 7.38 - 7.23 (m, 6H), 7.17 (dd, J =9.0, 2.5 Hz, 1H), 7.12 (d, J = 9.7 Hz, 1H), 5.18 (s, 2H), 4.37 (dd, J = 8.6, 6.3 Hz, 1H), 4.26 - 4.19 (m, 2H), 4.12 (d, J = 3.1 Hz, 1H), 3.90 (s, 3H), 3.85 (dd, J = 3.9, 2.3 Hz, 2H), 3.75 (td, J = 7.6, 3.1 Hz, 1H), 3.71 - 3.65 (m, 2H), 3.64 - 3.57 (m, 2H), 3.52 (t, J = 5.5 Hz, 2H), 3.42 - 3.35 (m, 1H), 3.34 - 3.31 (m, 1H), 3.09 (dd, J = 13.9, 7.9 Hz, 1H), 2.90 (dd, J = 13.9, 7.1 Hz, 1H), 1.88 - 1.47 (m, 3H), 0.94 (d, J = 6.3 Hz, 3H), 0.92 (d, J = 6.4 Hz, 3H). Tr(METCR1603) = 4.01 min, (ES) + [M+H] + 772. 【0253】 [Example 5] Scheme for Example 5 【0254】 [ka] 【0255】 Step 1: 6-Oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydropyridazine-3-carboxylic acid Methyl 6-oxo-1,6-dihydropyridazine-3-carboxylate (2.00 g, 12.98 mmol) was dissolved in dry DMF (17.5 mL), cooled to 0°C, and sodium hydride (60% dispersion in mineral oil, 779 mg, 19.46 mmol) was added gradually. The reaction mixture was stirred at 0°C for 5 minutes, then [2-(chloromethoxy)ethyl]trimethylsilane (2.76 mL, 15.57 mmol) was added over 5 minutes, and the resulting mixture was stirred at 0°C for 1 hour. The reaction mixture was then poured into ice-cold water and extracted with DCM. The aqueous layer was acidified to approximately pH 4 and extracted with DCM (3×). The organic layers from both extracts were combined and evaporated to dryness to obtain a dark red crude oil, which was dissolved in a water:MeOH mixture (1:1, 30 mL) and treated with LiOH.H2O (653 mg, 15.57 mmol). The reaction mixture was stirred at room temperature for 1 hour, then concentrated to reduce its volume, and acidified to approximately pH 4 with a 10% solution of citric acid (aq). The aqueous phase was extracted with DCM, the combined extract was washed with brine, dried over Na2SO4, filtered, and evaporated to dryness to obtain the title compound. 1 H NMR (250 MHz, DMSO-d6) δ 7.84 (d, J = 9.7 Hz, 1H), 7.03 (d, J = 9.7 Hz, 1H), 5.38 (s, 2H), 3.77 - 3.55 (m, 2H), 0.97 - 0.81 (m, 2H), -0.04 (s, 9H). Tr(METCR1410) = 1.03 minutes, (ES + ) [M+Na] + 293. 【0256】 Step 2: N-(2-hydroxy-5-nitrophenyl)-6-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydropyridazine-3-carboxamide 2-amino-4-nitrophenol (500 mg, 3.244 mmol) and 1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (1.06 g, 13.569 mmol) were combined in pyridine (8 mL) and stirred until dissolved. EDC-HCl (808 mg, 4.22 mmol) was added all at once, and the reaction mixture was stirred overnight. Water was added to the reaction mixture, the precipitated solid was filtered, and washed with water. The crude residue was partitioned between water and toluene. The aqueous layer was extracted with toluene (3 × 15 mL), the combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated to dryness. The solid was further purified by FCC (silica, 0-10% MeOH in DCM) to obtain the title compound. 1 H NMR (250 MHz, chloroform-d) δ 9.34 (s, 1H), 8.41 (d, J = 2.7 Hz, 1H), 8.06 (dd, J = 9.0, 2.7 Hz, 1H), 8.04 (d, J = 9.7 Hz, 1H), 7.10 (d, J = 9.8 Tr(METCR1410) = 1.16 min, ES + It does not ionize in that state. 【0257】 Step 3: 6-(5-nitro-1,3-benzoxazol-2-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydropyridazine-3-one N-(2-hydroxy-5-nitrophenyl)-6-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydropyridazine-3-carboxamide (600 mg, 1.476 mmol), triphenylphosphine (774 mg, 2.952 mmol), and hexachloroethane (874 mg, 3.690 mmol) were suspended in DCM (30 mL) at room temperature. Triethylamine (823 μL, 5.904 mmol) was added, and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted in DCM and washed with water and brine. The organic layer was dried over MgSO4, filtered, and adsorbed onto silica. The crude product was purified by FCC (silica, heptane, 0-50% ethylethanol) to obtain the title compound. 1 H NMR (250 MHz, chloroform-d) δ 8.70 (dd, J = 2.3, 0.5 Hz, 1H), 8.40 (dd, J = 9.0, 2.3 Hz, 1H), 8.15 (d, J = 9.8 Hz, 1H), 7.76 (dd, J = 9.0, 0.5 Hz, 1H), 7.12 (d, J = 9.8 Hz, 1H), 5.63 (s, 2H), 3.89 - 3.66 (m, 2H),1.15 - 0.90 (m, 2H), 0.01 (s, 9H). Tr(METCR1410) = 1.34 min, (ES + ) [M+Na] + 411. 【0258】 Step 4: 6-(5-nitro-1,3-benzoxazol-2-yl)-2,3-dihydropyridazine-3-one TFA (1.00 mL, 13.06 mmol) was added dropwise to a solution of 6-(5-nitro-1,3-benzoxazole-2-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydropyridazine-3-one (100 mg, 0.257 mmol) in DCM (10 mL), and the mixture was stirred overnight at room temperature. The reaction product was quenched with a saturated solution of NaHCO3 (aq). The organic solvent was removed under vacuum, and the precipitated yellow solid was ground in aqueous solution for 5 minutes and then filtered. The solid was then dried under vacuum at 40°C for 5 hours to obtain the title compound. 1H NMR (250 MHz, DMSO-d6) δ 13.80 (s, 1H), 8.72 (d, J = 2.3 Hz, 1H), 8.39 (dd, J = 9.0, 2.4 Hz, 1H), 8.14 (d, J = 9.9 Hz, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.10 (d, J = 9.9 Hz, 1H). Tr(METCR1600) = 2.38 minutes, (ES) + [M+H] + 259. 【0259】 Step 5: tert-butyl N-[2-(2-{2-[3-(5-nitro-1,3-benzoxazole-2-yl)-6-oxo-1,6-dihydropyridazine-1-yl]ethoxy}ethoxy)ethyl]carbamate K2CO3 (33 mg, 0.241 mmol) was added in one dose to a suspension of tert-butyl N-{2-[2-(2-iodoethoxy)ethoxy]ethyl}carbamate (75 mg, 0.209 mmol) and 6-(5-nitro-1,3-benzoxazole-2-yl)-2,3-dihydropyridazine-3-one (41 mg, 0.161 mmol) in DMF (1.5 mL). The reaction mixture was stirred at room temperature for 22 hours, then partitioned between water and ethyl acetate. The layers were separated, and the aqueous phase was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated to dryness. The crude product was purified by FCC (silica, 0-5% MeOH in DCM) to obtain the title compound. 1H NMR (250 MHz, chloroform-d) δ 8.67 (dd, J = 2.3, 0.5 Hz, 1H), 8.37 (dd, J = 9.0, 2.3 Hz, 1H), 8.13 (d, J = 9.7 Hz, 1H), 7.75 (dd, J = 9.0, 0.5 Hz, 1H), 7.09 (d, J = 9.8 Hz, 1H), 5.01 (s, 1H), 4.54 (t, J = 5.7 Hz, 2H), 3.98 (t, J = 5.7 Hz, 2H), 3.68 - 3.53 (m, 4H), 3.47 (t, J = 5.1 Hz, 2H), 3.25 (t, J = 6.8 Hz, 2H), 1.41 (s, 9H). Tr(METCR1410) = 1.15 minutes, (ES) + [M-BOC] + 390. 【0260】 Step 6: tert-butyl N-[2-(2-{2-[3-(5-amino-1,3-benzoxazole-2-yl)-6-oxo-1,6-dihydropyridazine-1-yl]ethoxy}ethoxy)ethyl]carbamate Iron powder (96 mg, 1.716 mmol) was added to a solution of NH4Cl (115 mg, 2.145 mmol) and tert-butyl N-[2-(2-{2-[3-(5-nitro-1,3-benzoxazole-2-yl)-6-oxo-1,6-dihydropyridazine-1-yl]ethoxy}ethoxy)ethyl]carbamate (210 mg, 0.429 mmol) in EtOH (10 mL) and water (1 mL). The mixture was heated under reflux for 3 hours, then cooled to room temperature and filtered through Celite. The filtrate was evaporated to dryness, the residue was diluted with siRNA / water and extracted with siRNA (3 × 15 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated to dryness to obtain the title compound. 1H NMR (250 MHz, chloroform-d) δ 8.10 (d, J = 9.8 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.15 - 6.89 (m, 2H), 6.77 (dd, J = 8.7, 2.3 Hz, 1H), 5.05 (s, Tr(METCR1410) = 0.93 minutes, (ES) + [M+H] + 460. 【0261】 Step 7: tert-butyl N-{2-[2-(2-{3-[5-(5-methoxypyridine-2-amide)-1,3-benzoxazole-2-yl]-6-oxo-1,6-dihydropyridazine-1-yl}ethoxy)ethoxy]ethyl}carbamate HATU (172 mg, 0.453 mmol) was added to a stirred solution of DIPEA (197 μL, 1.132 mmol), tert-butyl N-[2-(2-{2-[3-(5-amino-1,3-benzoxazole-2-yl)-6-oxo-1,6-dihydropyridazine-1-yl]ethoxy}ethoxy)ethyl]carbamate (204 mg, 0.377 mmol), and 5-methoxypyridine-2-carboxylic acid (61 mg, 0.377 mmol) in THF (6 mL) at 0°C. The mixture was stirred at room temperature for 6 hours. The reaction product was then extracted in RINKAN (15 mL) and washed sequentially with 10% citrate (aq) solution, saturated NaHCO3 (aq) solution, and brine. The organic layer was dried over MgSO4, filtered, and evaporated to dryness. The crude product was purified by FCC (silica, 0-4% MeOH in DCM) to obtain the title compound. 1H NMR (500 MHz, chloroform-d) δ 9.99 (s, 1H), 8.38 - 8.23 ​​(m, 3H), 8.16 (d, J = 9.7 Hz, 1H), 7.76 (dd, J = 8.9, 2.1 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.36 (dd, J = 8.7, 2.9 Hz, 1H), 7.07 (d, J = 9.7 Hz, 1H), 5.06 (s, 1H), 4.55 (t, J = 5.8 Hz, 2H), 4.00 (t, J = 5.9 Hz, 2H), 3.96 (s, 3H), 3.70 - 3.66 (m, Tr(METCR1410) = 1.18 min, (ES) + [M+H] + 595. 【0262】 Step 8: N-[2-(1-{2-[2-(2-azaniumylethoxy)ethoxy]ethyl}-6-oxo-1,6-dihydropyridazine-3-yl)-1,3-benzoxazole-5-yl]-5-methoxypyridine-2-carboxamide chloride HCl (4N in dioxane, 1.50 mL, 6.00 mmol) was added dropwise to a solution of tert-butyl N-{2-[2-(2-{3-[5-(5-methoxypyridine-2-amide)-1,3-benzoxazole-2-yl]-6-oxo-1,6-dihydropyridazine-1-yl}ethoxy)ethoxy]ethyl}carbamate (65 mg, 0.109 mmol) in MeOH (0.5 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was then evaporated to dryness to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.47 (d, J = 2.0 Hz, 1H), 8.41 (d, J = 2.8 Hz, 1H), 8.19 (d, J = 9.6 Hz, 1H), 8.17 (d, J = 8.7 Hz, 1H), 8.00 (dd, J = 8.9, 2.1 Hz, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.80 (s, 3H), 7.64 (dd, J = 8.7, 2.9 Hz, 1H), 7.17 (d, J = 9.7 Hz, 1H), 4.40 (t, J = 5.7 Hz, 2H), 3.95 (s, 3H), 3.87 (t, J = 5.7 Hz, 2H), 3.70 - 3.51 (m, 6H), 2.91 (q, J = 5.5 Hz, 2H). Tr(METCR1410) = 0.92 min, (ES) + [M+H] + 494. 【0263】 Step 9: tert-butyl N-[(1S,2R)-1-hydroxy-1-{[(1S)-1-({2-[2-(2-{3-[5-(5-methoxypyridine-2-amide)-1,3-benzoxazole-2-yl]-6-oxo-1,6-dihydropyridazine-1-yl}ethoxy)ethoxy]ethyl}carbamoyl)-3-methylbutyl]carbamoyl}-3-phenylpropane-2-yl]carbamate DIPEA (160 μL, 0.918 mmol) was added to a suspension of N-[2-(1-{2-[2-(2-azaniumylethoxy)ethoxy]ethyl}-6-oxo-1,6-dihydropyridazine-3-yl)-1,3-benzoxazole-5-yl]-5-methoxypyridine-2-carboxamide chloride (75 mg, 0.141 mmol), (2S)-2-[[(2S,3R)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenyl-butanoyl]amino]-4-methylpentanoic acid (60 mg, 0.141 mmol), EDC.HCl (108 mg, 0.565 mmol), and HOBT (49 mg, 0.318 mmol), which had been stirred at 0°C. The resulting mixture was stirred at 0°C and then heated to room temperature for 2 hours. The reactants were partitioned between water and toluene. The organic layer was successively washed with 10% citric acid solution (aq), saturated NaHCO3 (aq), and brine. The organic phase was dried over MgSO4, filtered, and evaporated to dryness to obtain the title compound. 1H NMR (500 MHz, chloroform-d) δ 10.00 (s, 1H), 8.33 - 8.24 (m, 3H), 8.16 (d, J = 9.7 Hz, 1H), 7.76 (dd, J = 8.8, 2.2 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.36 (dd, J = 8.7, 2.9 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.25 - 7.15 (m, 5H), 7.06 (d, J = 9.7 Hz, 1H), 6.88 (s, 1H), 5.51 (s, 1H), 5.08 (d, J = 8.6 Hz, 1H), 4.61 - 4.43 (m, 3H), 4.20 - 4.07 (m, 2H), 4.02 - 3.92 (m, 5H), 3.61 (d, J = 4.4 Hz, 2H), 3.56 - 3.41 (m, 5H), 3.35 - 3.25 (m, 1H), 3.12 - 2.96 (m, 2H), 1.74 (td, J = 8.7, 4.4 Hz, 1H), 1.63 - 1.52 (m, 2H), 1.36 (s, 9H), 0.93 (d, J = 6.4 Hz, 3H), 0.90 (s, 3H). Tr(MET-uHPLC-AB-101) = 3.79 minutes, (ES) + [M+H] + 885. 【0264】 Step 10: N-(2-{1-[2-(2-{2-[(2S)-2-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutanamide]-4-methylpentanamide]ethoxy}ethoxy)ethyl]-6-oxo-1,6-dihydropyridazine-3-yl}-1,3-benzoxazole-5-yl)-5-methoxypyridine-2-carboxamide (Compound 50) HCl (4N in dioxane, 2.00 mL, 8.00 mmol) was added dropwise to a stirred suspension of tert-butyl N-[(1S,2R)-1-hydroxy-1-{[(1S)-1-({2-[2-(2-{3-[5-(5-methoxypyridine-2-amide)-1,3-benzoxazole-2-yl]-6-oxo-1,6-dihydropyridazine-1-yl}ethoxy)ethoxy]ethyl}carbamoyl)-3-methylbutyl]carbamoyl}-3-phenylpropane-2-yl]carbamate (98 mg, 0.099 mmol) in MeOH (1.0 mL). The mixture was stirred at room temperature for 2.5 hours. The reaction mixture was then evaporated to dryness and purified by chiral prep HPLC (methanol, using a Chiralcel OJ-H 25cm column at 15 mL / min) to obtain the title compound. 1 H NMR (500 MHz, methanol-d4) δ 8.38 (t, J = 2.5 Hz, 2H), 8.23 ​​(d, J = 9.7 Hz, 1H), 8.19 (d, J = 8.7 Hz, 1H), 7.77 (dd, J = 8.8, 2.1 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.55 (dd, J = 8.7, 2.9 Hz, 1H), 7.31 - 7.10 (m, 6H), 4.50 (dd, J = 6.2, 4.9 Hz, 2H), 4.40 (dd, J = 9.1, 5.5 Hz, 1H), 4.01 - 3.95 (m, 5H), 3.93 (d, J = 3.1 Hz, 1H), 3.69 - 3.59 (m, 2H), 3.57 - 3.49 (m, 2H), 3.45 (t, J = 5.5 Hz, 2H), 3.28 (td, J = 5.4, 2.5 Hz, 3H), 2.89 (dd, J = 13.4, 6.9 Hz, 1H), 2.65 (dd, J = 13.4, 7.8 Hz, 1H), 1.68 - 1.51 (m, 3H), 0.93 (d, J = 6.1 Hz, 3H), 0.91 (d, J = 6.2 Hz, 3H). Tr(METCR1603) = 4.20 minutes, (ES) + [M+H] + 785. 【0265】 [Example 6] Scheme for the Example Reference 【0266】 [ka] 【0267】 Step 1: Methyl 5-(2-{2-[3-(tert-butoxy)-3-oxopropoxy]ethoxy}ethoxy)pyridine-2-carboxylate A solution of methyl 5-hydroxypyridine-2-carboxylate (400 mg, 2.61 mmol) and tert-butyl 3-[2-(2-hydroxyethoxy)ethoxy]propanoate (673 mg, 2.87 mmol) in THF (15.0 mL) was cooled to 0°C and treated with triphenylphosphine (1.03 g, 3.92 mmol). The reaction mixture was stirred for 20 minutes, then treated dropwise with DIAD (0.77 mL, 3.92 mmol). The mixture was stirred at 0°C for a further 30 minutes, then at room temperature overnight. The reaction mixture was then concentrated to dryness, and the crude product was dissolved in RINKAN (100 mL). The organic layer was washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure to obtain a brown oily substance, which was purified by FCC (silica, heptane, 10-45% RINKAN) to obtain the title compound. 1 H NMR (500 MHz, chloroform-d) δ 8.41 (d, J = 2.8 Hz, 1H), 8.10 (d, J = 8.7 Hz, 1H), 7.28 (dd, J = 8.7, 2.9 Hz, 1H), 4.25 - 4.21 (m, 2H), 3.97 (s, Tr (METCR1410) = 1.08 minutes, (ES + ) [M+H] + 370. 【0268】 Step 2: 5-(2-{2-[3-(tert-butoxy)-3-oxopropoxy]ethoxy}ethoxy)pyridine-2-carboxylic acid To a solution of 2-(aminomethyl)-5-(4-methylthiazole-5-yl)phenol (400 mg, 0.563 mmol) in THF (3 mL) and MeOH (3 mL), 1 M NaOH (1.13 mL, 1.13 mmol) was added, and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was neutralized with 1 M HCl (1.13 mL) at 0°C, and the solvent was then removed under vacuum. MeCN (2.0 mL) was added, and the crude product was purified by reverse-phase chromatography (C-18, 10-100% MeCN / water + 0.1% formic acid). The pure fractions were combined, and the solvent was removed under vacuum to obtain the title compound. Tr (METCR1410) = 0.96 min, (ES + ) [M+H] + 356. 【0269】 Step 3: tert-butyl3-(2-{2-[(6-{[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazole-5-yl]carbamoyl}pyridine-3-yl)oxy]ethoxy}ethoxy)propanoate A stirred solution of 5-(2-{2-[3-(tert-butoxy)-3-oxopropoxy]ethoxy}ethoxy)pyridine-2-carboxylic acid (175 mg, 0.49 mmol) and HATU (224 mg, 0.59 mmol) in DMF (5 mL) under nitrogen at 0°C was treated by dropwise addition of DIPEA (0.19 mL, 1.08 mmol). The reaction mixture was stirred at 0°C for 15 minutes and then treated with 6-(5-amino-1,3-benzoxazole-2-yl)-2-methylpyridazine-3-one (120 mg, 0.49 mmol). The resulting mixture was stirred at 0°C for 1 hour, then at room temperature over the weekend. The reaction mixture was then concentrated under vacuum, the residue was suspended in water (30 mL), and the suspension was stirred at room temperature for 30 minutes. The solid was filtered, washed with water and TBME (10 mL), and then dried overnight in a high-vacuum oven at 40°C to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.48 - 8.37 (m, 2H), 8.19 - 8.10 (m, 2H), 7.97 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 6.4 Hz, 1H), 7.13 (d, J = 9.7 Hz, 1H), 4.29 (s, 2H), 3.85 - 3.77 (m, 5H), 3.63 - 3.50 (m, 6H), 2.41 (t, J = 6.1 Hz, 2H), 1.38 (s, 9H). Tr (METCR1410) = 1.19 minutes, (ES + ) [M+H] + 580. 【0270】 Step 4: 3-(2-{2-[(6-{[2-(1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)-1,3-benzoxazole-5-yl]carbamoyl}pyridine-3-yl)oxy]ethoxy}ethoxy)propanoic acid A stirred solution of tert-butyl 3-(2-{2-[(6-{[2-(1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)-1,3-benzoxazole-5-yl]carbamoyl}pyridine-3-yl)oxy]ethoxy}ethoxy)propanoate (215 mg, 0.36 mmol) in DCM (5.0 mL) was treated with TFA (0.14 mL, 1.8 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was then retreated with TFA (0.28 mL, 3.6 mmol) and stirred for a further 24 hours at room temperature. The reaction mixture was then concentrated under vacuum, the residue was diluted with water (10 mL), and neutralized at 0°C with a saturated solution of NaHCO3(aq). The precipitated solid was filtered, washed with water, and then dried in a high-vacuum oven at 40°C for 4 hours to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.48 - 8.40 (m, 2H), 8.17 (dd, J = 14.1, 9.2 Hz, 2H), 7.99 (d, J = 8.7 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.65 (dd, J = 8.6, 2.5 Hz, 1H), 7.15 (d, J = 9.7 Hz, 1H), 4.30 (m, 2H), 3.81 (m, 5H), 3.67 - 3.58 (m,4H), 3.54 (m, 2H), 2.45 (t, J = 6.3 Hz, 2H). (METCR1410 General 2 minutes) = 0.97 minutes, (ES + ) [M+H] + 524. 【0271】 Step 5: 5-{2-[2-(2-{[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazole-5-yl)phenyl]methyl}carbamoyl)pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}ethoxy)ethoxy]ethoxy}-N-[2-(1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)-1,3-benzoxazole-5-yl]pyridine-2-carboxamide A stirred solution of 3-(2-{2-[(6-{[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazole-5-yl]carbamoyl}pyridine-3-yl)oxy]ethoxy}ethoxy)propanoic acid (80 mg, 0.15 mmol) and HATU (87 mg, 0.23 mmol) in DMF (2.5 mL) was stirred under nitrogen at 0°C and treated by dropwise addition of DIPEA (0.066 mL, 0.38 mmol). The reaction mixture was stirred at 0°C for 15 minutes, and then treated with (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazole-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (78 mg, 0.17 mmol). The resulting mixture was stirred at 0°C for 1 hour, then at room temperature over the weekend. The reaction mixture was then purified directly by low pH prep-HPLC. The pure fractions were combined, the precipitated solid was filtered off, and the mixture was further dried in a vacuum oven at 50°C for several hours to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) 10.73 (s, 1H), 8.98 (s, 1H), 8.55 (t, J = 6.1 Hz, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 2.8 Hz, 1H), 8.19 (d, J = 9.7 Hz, 1H), 8.16 (d, J = 8.7 Hz, 1H), 7.99 (dd, J = 8.9, 2.1 Hz, 1H), 7.91 (d, J = 9.4 Hz, 1H), 7.82 (d, J = 8.9 Hz, 1H), 7.64 (dd, J = 8.8, 2.9 Hz, 1H), 7.44 - 7.36 (m, 4H), 7.15 (d, J = 9.7 Hz, 1H), 5.13 (d, J = 3.5 Hz, 1H), 4.56 (d, J = 9.4 Hz, 1H), 4.47 - 4.39 (m, 2H), 4.38 - 4.34 (m, 1H), 4.32 - 4.27 (m, 2H), 4.23 (dd, J = 15.8, 5.5 Hz, 1H), 3.84 - 3.78 (m, 5H), 3.70 - 3.50 (m, 8H), 2.59 - 2.53 (m, 1H), 2.44 (s, 3H), 2.41 - 2.33 (m, 1H), 2.08 - 2.00 (m, 1H), 1.94 - 1.88 (m, 1H), 0.94 (s, 9H). Tr(METCR1603) = 3.87 minutes, (ES + ) (M+H) + 936.7. 【0272】 The following compounds were prepared as described above. 【0273】 [Table 6] TIFF0007872824000055.tif218170TIFF0007872824000056.tif114170 【0274】 [Example 7] Scheme for Example 7 【0275】 [ka] 【0276】 Step 1: 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl 4-methylbenzene sulfonate A stirred solution of 2,2'-[oxybis(ethane-2,1-diyloxy)]diethanol (7.28 g, 37.5 mmol) in THF (2 mL) was cooled to 0°C (ice / water), treated with finely crushed sodium hydroxide (0.23 g, 5.72 mmol), and a solution of 4-methylbenzenesulfonyl chloride (0.69 g, 3.62 mmol) in THF (20 mL) was subsequently added dropwise over 10 minutes. The resulting mixture was stirred at 0°C for 3 hours. The reaction mixture was then poured into an ice / water mixture (75 mL) and dissolved. The layers were separated, and the aqueous phase was extracted with DCM (3 × 40 mL). The combined organic layers were washed with water (50 mL) and brine (2 × 50 mL), dried over MgSO4, filtered, and concentrated under vacuum. The crude material was pre-absorbed onto silica and purified by FCC (silica, heptane 0-100% ethyl phosphate). The clean fractions were combined, concentrated in a vacuum, and further dried under high vacuum to obtain the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 7.78 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 4.55 (t, J = 5.1 Hz, 1H), 4.11 (dd, J = 5.1, 3.7 Hz, 2H), 3.60 - 3.54 (m, 2H), 3.52 - 3.46 (m, 6H), 3.45 (s, 4H), 3.40 (t, J = 5.2 Hz, 2H), 2.42 (s, 3H). Tr(METCR1410)= 0.97 min, (ES+) (M+H)+ 349. 【0277】 Step 2: 2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethanol A stirred solution of 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (447 mg, 1.28 mmol) in acetone (10 mL) was treated with sodium iodide (971 mg, 6.41 mmol) and stirred at 70°C for 1.5 hours. The reaction mixture was then cooled to room temperature, filtered through Celite, and the cake was washed with acetone (10 mL). The filtrate was concentrated under vacuum, the residue was dissolved in DCM (15 mL), washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered, concentrated under vacuum, and further dried under high vacuum to obtain the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 4.55 (t, J = 5.5 Hz, 1H), 3.66 (t, J = 6.4 Hz, 2H), 3.56 (dd, J = 5.5, 2.9 Hz, 2H), 3.54 - 3.51 (m, 6H), 3.49 (q, J = 5.1 Hz, 2H), 3.42 (t, J = 5.1 Hz, 2H), 3.33 (s, 2H). Tr(METCR1410) = 0.81 min, (ES + ) (M+H) + 305. 【0278】 Step 3: Methyl 5-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]pyridine-2-carboxylate A stirred solution of methyl 5-hydroxypyridine-2-carboxylate (52 mg, 0.34 mmol) and 2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethanol (113 mg, 0.37 mmol) in THF (8 mL) was cooled to 0°C and treated with triphenylphosphine (134 mg, 0.51 mmol). The reaction mixture was stirred for 10 minutes, and then treated dropwise with a solution of DIAD (100 μL, 0.51 mmol) in THF (5 mL) for 10 minutes. The mixture was stirred at 0°C for a further 43 minutes, then at room temperature overnight. The reaction product was then concentrated to dryness to obtain the product, which was then purified by acid reverse-phase chromatography (C-18, 10-100% MeCN / water + 0.1% formic acid) to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ 8.39 (d, J = 2.9 Hz, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.53 (dd, J = 8.7, 2.9 Hz, 1H), 4.31 - 4.25 (m, 2H), 3.84 (s, 3H), 3.81 - 3.76 (m, 2H), 3.65 (t, J = 6.4 Hz, 2H), 3.60 (dd, J = 5.9, 3.2 Hz, 2H), 3.54 (ddq, J = 7.5, 5.4, 2.8 Hz, 6H), 3.29 (s, 2H). Tr(METCR1410) = 1.04 minutes, (ES + ) (M+H) + 439. 【0279】 Step 4: 5-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]pyridine-2-carboxylic acid A stirred solution of methyl 5-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]pyridine-2-carboxylate (96.4 mg, 0.22 mmol) in THF (2 mL) was treated with a solution of 1 M LiOH (0.98 mL). The mixture was stirred at room temperature for 4 hours. The reaction mixture was then concentrated under vacuum, and the remaining aqueous substance was extracted with ether (3 × 5 mL). The aqueous phase was then acidified to pH 4 by adding a solution of 10% citric acid (1.5 mL). The mixture was extracted with ELISA (3 × 15 mL). The combined organic extract was washed with brine (15 mL), dried over MgSO4, filtered, concentrated under vacuum, and then further dried overnight in a high-vacuum oven at 50°C to room temperature to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ 12.71 (s, 1H), 8.38 (d, J = 2.9 Hz, 1H), 8.01 (d, J = 8.7 Hz, 1H), 7.52 (dd, J = 8.7, 2.9 Hz, 1H), 4.30 - 4.24 (m, 2H), 3.81 - 3.76 (m, 2H), 3.65 (t, J = 6.4 Hz, 2H), 3.60 (dd, J = 6.1, 3.4 Hz, 2H), 3.54 (ddq, J = 7.4, 5.3, 2.8 Hz, 6H), 3.30 (s, 2H). Tr(METCR1410) = 0.93 minutes, (ES + ) (M+H) + 426. 【0280】 Step 5: 5-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]-N-[2-(1-methyl-6-oxopyridazine-3-yl)-1,3-benzoxazole-5-yl]pyridine-2-carboxamide A stirred solution of 5-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]pyridine-2-carboxylic acid (74 mg, 0.17 mmol) and N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridine-3-yloxy)methylidene]-N-methylmethaneaminium hexafluorophosphate (84 mg, 0.22 mmol) in DMF (2 mL) was cooled to 0°C and treated with N-ethyl-N-(propan-2-yl)propan-2-amine (70 μL, 0.40 mmol). The resulting mixture was stirred for 8 minutes and then treated with 6-(5-amino-1,3-benzoxazole-2-yl)-2-methylpyridazine-3-one (44 mg, 0.18 mmol). The mixture was stirred at 0°C for 1 hour, then at room temperature overnight. The reaction mixture was then concentrated under vacuum and partitioned between water (10 mL) and DCM (10 mL). The layers were separated, and the aqueous phase was extracted with DCM (3 × 10 mL). The combined organic phase was washed with a saturated solution of NaHCO3 (10 mL). The layers were separated, and the aqueous phase was extracted with DCM (10 mL). The combined organic phase was washed with brine (10 mL). The layers were separated, and the aqueous phase was extracted with DCM (10 mL). The combined organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude material was purified by FCC (silica, heptane with 0-100% ethyl phosphate, followed by a flash of 10% MeOH in DCM), and then subjected to acid reverse-phase chromatography (C-18, 10-100% MeCN / water + 0.1% formic acid). The clean fractions were combined, concentrated in a vacuum, and further dried overnight in a vacuum oven at 50°C to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 2.8 Hz, 1H), 8.18 (d, J = 9.7 Hz, 1H), 8.15 (d, J = 8.7 Hz, 1H), 7.99 (dd, J = 8.9, 2.1 Hz, 1H), 7.82 (d, J = 8.9 Hz, 1H), 7.65 (dd, J = 8.8, 2.9 Hz, 1H), 7.15 (d, J = 9.7 Hz, 1H), 4.34 - 4.28 (m, 2H), 3.81 (s, 5H), 3.66 (t, J = 6.4 Hz, 2H), 3.62 (dd, J = 6.1, 3.4 Hz, 2H), 3.59 - 3.56 (m, 2H), 3.55 (dq, J = 4.7, 2.7, 1.9 Hz, 4H), 3.30 (s, 2H). Tr(METCR1410) = 1.18 minutes, (ES) + (M+H) + 650. 【0281】 Step 6: 5-{2-[2-(2-{2-[2-({[(2S,4R)-4-hydroxy-1-[(2S)-3-methyl-2-(1-oxo-2,3-dihydro-1H-isoindole-2-yl)butanoyl]pyrrolidine-2-yl]formamide}methyl)-5-(4-methyl-1,3-thiazole-5-yl)phenoxy]ethoxy}ethoxy)ethoxy]ethoxy}-N-[2-(1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)-1,3-benzoxazole-5-yl]pyridine-2-carboxamide The sealed tube was filled with a solution of (4R)-4-hydroxy-N-[[2-hydroxy-4-(4-methylthiazole-5-yl)phenyl]methyl]-1-[3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl]pyrrolidine-2-carboxamide (45.75 mg, 0.08 mmol) in DMF (1 mL), and K2CO3 (19.21 mg, 0.14 mmol) was added. The suspension was stirred at room temperature for 10 minutes, then treated with a solution of 5-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]-N-[2-(1-methyl-6-oxopyridazin-3-yl)-1,3-benzoxazole-5-yl]pyridine-2-carboxamide (36 mg, 0.06 mmol) in DMF (1.5 mL). The resulting suspension was stirred at 70°C for 5 hours, then allowed to cool to room temperature. The reaction mixture was concentrated under vacuum, and the residue was partitioned between water (10 mL) and DCM (10 mL). The layers were separated, and the aqueous phase was extracted with DCM (3 × 10 mL). The combined organic matter was washed with brine (10 mL). The layers were separated, and the aqueous substance was extracted with DCM (10 mL). The combined organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude material was purified by acid reverse-phase chromatography (C-18, 10-100% MeCN / water + 0.1% formic acid). The clean fraction was ground with ether and then re-purified by acid reverse-phase chromatography (C-18, 10-100% MeCN / water + 0.1% formic acid). The clean fraction was freeze-dried overnight to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) 10.72 (s, 1H), 8.97 (s, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.41 (d, J = 2.8 Hz, 1H), 8.35 (t, J = 5.8 Hz, 1H), 8.18 (d, 7.67 - 7.57 (m, 3H), 7.49 (t, J = 8.0 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.14 (d, J = 9.7 Hz, 1H), 7.04 (d, J = 1.4 Hz, 1H), 7.00 (dd, J = 7.8, 1.4 Hz, 1H), 5.08 (d, J = 3.6 Hz, 1H), 4.71 (d, J = 10.8 Hz, 1H), 4.54 (d, J = 18.1 Hz, 1H), 4.45 (d, J = 18.4 Hz, 1H), 4.41 (t, J = 8.0 Hz, 1H), 4.36 - 4.31 (m, 1H), 4.31 - 4.20 (m, 4H), 4.21 - 4.15 (m, 2H), 3.86 - 3.74 (m, 8H), 3.69 (d, J = 9.9 Hz, 1H), 3.66 - 3.60 (m, 2H), 3.62 - 3.57 (m, 2H), 3.59 - 3.54 (m, 4H), 2.46 (s, 3H), 2.36 - 2.26 (m, 1H), 2.09 - 2.00 (m, 1H), 1.97 - 1.87 (m, 1H), 0.96 (d, J = 6.5 Hz, 3H), 0.73 (d, J = 6.6 Hz, 3H). Tr(MET-uHPLC-AB-101) = 3.2 points, (ES + (M+H) + 1070. 【0282】 The following compounds are the same as those mentioned above. 【0283】 [Table 7] 【0284】 [Example 8] Scheme for Example 8 【0285】 [ka] 【0286】 Step 1: tert-butyl 2-[2-[2-[[6-[[2-(1-methyl-6-oxopyridazin-3-yl)-1,3-benzoxazole-5-yl]oxymethyl]-3-pyridyl]oxy]ethoxy]ethoxy]acetate A stirred suspension of 6-[5-[(5-hydroxy-2-pyridyl)methoxy]-1,3-benzoxazole-2-yl]-2-methylpyridazine-3-one (160 mg, 0.46 mmol) and tert-butyl 2-[2-(2-hydroxyethoxy)ethoxy]acetate (101 mg, 0.46 mmol) in a mixture of THF (10 mL) and DMF (2 mL) was cooled to 0°C and treated with triphenylphosphine (180 mg, 0.69 mmol). The reaction mixture was stirred for 10 minutes, and then treated dropwise with a solution of DIAD (134 μL, 0.69 mmol) in THF (5 mL) for 10 minutes. The mixture was stirred at 0°C for a further 16 minutes, and then at room temperature overnight. The reaction mixture was then concentrated under vacuum, treated with a solution of tert-butyl 2-[2-(2-hydroxyethoxy)ethoxy]acetate (101 mg, 0.46 mmol) in DMF (2 mL), cooled to 0°C, and treated with triphenylphosphine (180 mg, 0.69 mmol). The reaction mixture was stirred for 5 minutes, then treated dropwise with a solution of DIAD (134 μL, 0.69 mmol) in DMF (1 mL) for 2 minutes. The mixture was stirred for a further 23 minutes at 0°C, then at room temperature overnight. The reaction mixture was then treated with a solution of tert-butyl 2-[2-(2-hydroxyethoxy)ethoxy]acetate (50 mg, 0.23 mmol) in DMF (1 mL), cooled to 0°C, and treated with triphenylphosphine (90 mg, 0.34 mmol). The reaction mixture was stirred for 10 minutes, and then treated dropwise with a solution of DIAD (67 μL, 0.34 mmol) in DMF (1 mL) for 3 minutes. The mixture was stirred for a further 15 minutes at 0°C, and then overnight at room temperature. The reaction mixture was then concentrated to dryness, and the crude material was purified by basic reverse-phase chromatography (C-18, 10-100% MeCN / H2O + 0.1% NH4OH) to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ 8.31 (d, J = 2.8 Hz, 1H), 8.13 (d, J = 9.7 Hz, 1H), 7.75 (d, J = 8.9 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.48 (d, J = 2.5 Hz, 1H), 7.45 (dd, J = 8.6, 2.9 Hz, 1H), 7.16 (dd, J = 9.0, 2.5 Hz, 1H), 7.14 (d, J = 9.7 Hz, 1H), 5.18 (s, 2H), 4.24 - 4.15 (m, 2H), 3.99 (s, 2H), 3.80 (s, 3H), 3.78 - 3.75 (m, 2H), 3.62 - 3.57 (m, 4H), 1.41 (s, 9H). Tr(METCR1603) = 4.28 min, (ES + ) (M+H) + 553. 【0287】 Step 2: 2-[2-[2-[[6-[[2-(1-methyl-6-oxopyridazin-3-yl)-1,3-benzoxazole-5-yl]oxymethyl]-3-pyridyl]oxy]ethoxy]ethoxy]acetic acid A stirred solution of tert-butyl 2-[2-[2-[[6-[[2-(1-methyl-6-oxopyridazin-3-yl)-1,3-benzoxazole-5-yl]oxymethyl]-3-pyridyl]oxy]ethoxy]ethoxy]acetate (111 mg, 0.2 mmol) in DCM (5.0 mL) was treated with TFA (0.08 mL, 1.01 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was then retreated with TFA (0.15 mL, 1.96 mmol), stirred for a further 6 hours at room temperature, and then concentrated under vacuum, azeotropically mixed with DCM (2 × 10 mL), and further dried in a vacuum oven at 50°C for several hours to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ 8.35 (d, J = 2.8 Hz, 1H), 8.13 (d, J = 9.7 Hz, 1H), 7.75 (d, J = 8.9 Hz, 1H), 7.57 - 7.47 (m, 3H), 7.17 (dd, J = 9.0, 2.5 Hz, 1H), 7.14 (d, J = 9.7 Hz, 1H), 5.21 (s, 2H), 4.24 - 4.18 (m, 2H), 4.01 (d, J = 8.4 Hz, 2H), 3.80 (s, 3H), 3.78 - 3.74 (m, 2H), 3.61 (s, 4H). Tr(METCR1410) = 0.96 minutes, (ES + ) (M+H) + 497. 【0288】 Step 3: (2S,4R)-1-[(2S)-3,3-dimethyl-2-{2-[2-(2-{[6-({[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazole-5-yl]oxy}methyl)pyridine-3-yl]oxy}ethoxy)ethoxy]acetamide}butanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazole-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide A stirred solution of 2-[2-[2-[[6-[[2-(1-methyl-6-oxopyridazin-3-yl)-1,3-benzoxazole-5-yl]oxymethyl]-3-pyridyl]oxy]ethoxy]ethoxy]acetic acid (50 mg, 0.1 mmol) and HATU (46 mg, 0.12 mmol) in DMF (2 mL) was cooled on ice and treated with DIPEA (88 μL, 0.5 mmol). The resulting solution was stirred for 16 minutes and then treated with (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazole-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (47 mg, 0.1 mmol). The mixture was stirred at 0°C for 1 hour, then at room temperature overnight. The reaction mixture was concentrated under vacuum, and the residue was partitioned between water (10 mL) and DCM (10 mL). The layers were separated, and the aqueous phase was extracted with DCM (3 × 10 mL). The combined organic layers were washed with a saturated solution of NaHCO3(aq) (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated under vacuum. The crude material was purified by basic reverse-phase chromatography (C-18, 10-100% MeCN / water + 0.1% NH4OH), followed by ether grinding (5 mL) to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) 8.95 (s, 1H), 8.60 (t, J = 6.0 Hz, 1H), 8.29 (d, J = 2.9 Hz, 1H), 8.13 (d, J = 9.7 Hz, 1H), 7.74 (d, J = 8.9 Hz, 1H), 7.50 - 7.46 (m, 2H), 7.45 - 7.40 (m, 2H), 7.40 - 7.34 (m, 4H), 7.18 - 7.11 (m, 2H), 5.16 (s, 2H), 5.14 (d, J = 3.1 Hz, 1H), 4.56 (d, J = 9.6 Hz, 1H), 4.44 (t, J = 8.2 Hz, 1H), 4.37 (dd, J = 15.9, 6.2 Hz, 2H), 4.26 (dd, J = 15.7, 5.8 Hz, 1H), 4.20 (t, J = 4.6 Hz, 2H), 4.03 - 3.92 (m, 2H), 3.84 - 3.75 (m, 5H), 3.71 - 3.57 (m, 6H), 2.41 (s, 3H), 2.11 - 2.01 (m, 1H), 1.94 - 1.86 (m, 1H), 0.90 (s, 9H). Tr(MET-uHPLC-AB-101) = 2.85 minutes, (ES + ) (M) + 909.3; (M+2H) / 2 + 455. 【0289】 The following compounds were prepared as described above. 【0290】 [Table 8] 【0291】 [Example 9] Scheme for Example 9 【0292】 [ka] 【0293】 Step 1: Methyl 5-{2-[2-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)ethoxy]ethoxy}pyridine-2-carboxylate A solution of methyl 5-hydroxypyridine-2-carboxylate (500 mg, 3.26 mmol) and tert-butyl N-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}carbamate (814 mg, 3.26 mmol) in THF (25.0 mL) was cooled to 0°C and treated with triphenylphosphine (1.28 g, 4.90 mmol). The reaction mixture was stirred for 20 minutes, then treated with DIAD (0.96 μL, 4.90 mmol) dropwise for 10 minutes. The mixture was stirred at 0°C for a further 30 minutes, then at room temperature overnight. The reaction mixture was then retreated with tert-butyl N-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}carbamate (407 mg, 1.63 mmol) and cooled to 0°C. PPh3 (0.64 g, 2.45 mmol) was added, the reaction mixture was stirred for 20 minutes, and then treated with DIAD (0.48 mL, 2.45 mmol). The mixture was stirred for a further 30 minutes at 0°C, and then for a further 24 hours at room temperature. The reaction mixture was then concentrated to dryness, and the crude product was dissolved in HCl (50 mL). The organic layer was extracted with HCl (2 × 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure to obtain the crude product, which was purified by FCC (silica, heptane 10-45% HCl, followed by DCM 1-8% MeOH) to obtain the title compound. 1H NMR (500 MHz, chloroform-d) δ 8.42 (d, J = 2.8 Hz, 1H), 8.10 (d, J = 8.7 Hz, 1H), 7.29 (dd, J = 8.7, 2.9 Hz, 1H), 4.95 (s, 1H), 4.28 - 4.23 (m, 2H), 3.98 (s, 3H), 3.90 (dd, J = 5.3, 4.1 Hz, 2H), 3.71 (dd, J = 5.7, 3.5 Hz, 2H), 3.64 (dd, J = 5.7, 3.5 Hz, 2H), 3.54 (t, J = 5.2 Hz, 2H), 3.35 - 3.27 (m, 2H), 1.43 (s, 9H). Tr(METCR1410) = 1.00 min, (ES + ) (M+H) + 385. 【0294】 Step 2: tert-butyl N-{2-[2-(2-{[6-(hydroxymethyl)pyridine-3-yl]oxyethoxy)ethoxy]ethyl}carbamate To a solution of methyl 5-{2-[2-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)ethoxy]ethoxy}pyridine-2-carboxylate (1.32 g, 3.02 mmol), LiAlH4 (1.89 mL, 4.53 mmol) was added dropwise at -10°C. The reaction mixture was heated to room temperature for 1 hour. The reaction mixture was cooled to 0°C and then quenched with 1 M NaOH until no more gas was produced. A saturated solution of NaHCO3 (20 mL) was added. The resulting suspension was filtered through a Celite pad, the solid was washed with ethyl acetate, the combined organic layer was washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude material was purified by FCC (silica, 10-45% ethyl acetate in heptane, followed by 0-100% {10% MeOH in DCM} / DCM) to obtain the title compound. 1H NMR (500 MHz, chloroform-d) δ 8.29 (s, 1H), 7.26 (m, 1H), 7.18 (d, J = 8.5 Hz, 1H), 5.02 (s, 1H), 4.70 (s, 2H), 4.22 - 4.17 (m, 2H), 3.90 - 3.84 (m, 2H), 3.71 (dd, J = 5.8, 3.3 Hz, 2H), 3.64 (dd, J = 5.6, 3.4 Hz, 2H), 3.54 (t, J = 5.1 Hz, 2H), 3.37 (s, 1H), 3.31 (d, J = 5.0 Hz, 2H), 1.43 (s, 9H). Tr(METCR1410) = 0.81 min, (ES + ) (M+H) + 357. 【0295】 Step 3: tert-butyl N-(2-{2-[2-({6-[(methanesulfonyloxy)methyl]pyridine-3-yl}oxy)ethoxy]ethoxy}ethyl)carbamate 350 mg, 0.66 mmol of tert-butyl N-{2-[2-(2-{[6-(hydroxymethyl)pyridine-3-yl]oxy}ethoxy)ethoxy]ethyl}carbamate was dissolved in 8.0 mL of DCM, then triethylamine (0.18 mL, 1.32 mmol) was added, and the solution was cooled to 0°C. Methanesulfonyl chloride (0.06 mL, 0.79 mmol) was added dropwise, and the mixture was stirred at 0°C for 2 hours. Methanesulfonyl chloride (0.06 mL, 0.79 mmol) was added dropwise, and the mixture was stirred at 0°C for a further 2 hours. 20 mL of water was carefully added to the cooled solution. The reaction mixture was heated to room temperature for 30 minutes, the phases were separated, and the aqueous phase was extracted with 2 × 10 mL of DCM. The organic phases were combined, dried over Na2SO4, filtered, and concentrated in vacuum to obtain the title compound, which was then used directly in the next step. Tr(METCR1410) = 1.04 min, (ES + ) (M+H) + 435. 【0296】 Step 4: tert-butyl N-{2-[2-(2-{[6-({[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazole-5-yl]oxy}methyl)pyridine-3-yl]oxy}ethoxy)ethoxy]ethyl}carbamate 6-(5-hydroxy-1,3-benzoxazole-2-yl)-2-methyl-2,3-dihydropyridazine-3-one (150 mg, 0.617 mmol) was dissolved in DMF (6.0 mL), and then Cs2CO3 (508 mg, 1.54 mmol) was added all at once. The reaction mixture was stirred at room temperature for 1 hour. A solution of tert-butyl N-(2-{2-[2-({6-[(methanesulfonyloxy)methyl]pyridine-3-yl}oxy)ethoxy]ethoxy}ethyl)carbamate (281 mg, 0.65 mmol) in DMF (2.0 mL) was added dropwise, and the reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was stirred at 45°C for a further 18 hours, and then the solvent was removed under vacuum. The residue was suspended in water (50 mL). The product was extracted with ELISA (3 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting residue was purified by FCC (silica, heptane with 0-50% RINKAN, then DCM with 0-10% MeOH), followed by basic reverse-phase chromatography (C-18, 10-100% MeCN / water + 0.1% NH4OH) to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ 8.32 (d, J = 2.8 Hz, 1H), 8.14 (d, J = 9.7 Hz, 1H), 7.75 (d, J = 8.9 Hz, 1H), 7.53 - 7.43 (m, 3H), 7.17 (dd, J = 9.0, 2.6 Hz, 1H), 7.14 (d, J = 9.7 Hz, 1H), 6.74 (s, 1H), 5.19 (s, 2H), 4.19 (dd, J = 5.3, 3.8 Hz, 2H), 3.80 (s, 3H), 3.76 (dd, J = 5.3, 3.8 Hz, 2H), 3.59 (dd, J = Tr(METCR1410) = 1.11 minutes, (ES + ) (M+H) + 582. 【0297】 Step 5: 6-{5-[(5-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}pyridine-2-yl)methoxy]-1,3-benzoxazole-2-yl}-2-methyl-2,3-dihydropyridazine-3-one 185 mg, 0.318 mmol of tert-butyl N-{2-[2-(2-{[6-({[2-(1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)-1,3-benzoxazole-5-yl]oxy}methyl)pyridine-3-yl]oxy}ethoxy)ethoxy]ethyl}carbamate was dissolved in 5.0 mL of DCM, and then 0.06 mL, 0.79 mmol of TFA was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched at 0°C with a saturated solution of NaHCO3 (aq). The aqueous phase was extracted with 3 × 20 mL of DCM. The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure to obtain a grayish-white solid (starting material). The white solid was dissolved in dioxane (4 mL), then 4 M HCl in dioxane (1.45 mL, 5.80 mmol) was added dropwise, and the suspension was stirred at room temperature for 4 hours. The solvent was removed under vacuum, the residue was dissolved in water (20 mL), and basicized with a saturated solution of NaHCO3 (aq). The aqueous phase was extracted with a solution of DCM:MeOH (5:1, 3 × 15 mL), the combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure to obtain the title compound. Tr(METCR1410) = 0.88 min, (ES + ) (M+H) + 482.5. 【0298】 Step 6: 2-(2,6-dioxopiperidine-3-yl)-4-({2-[2-(2-{[6-({[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazole-5-yl]oxy}methyl)pyridin-3-yl]oxy}ethoxy)ethoxy]ethyl}amino)-2,3-dihydro-1H-isoindole-1,3-dione The sealed tubes were filled with 6-{5-[(5-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}pyridine-2-yl)methoxy]-1,3-benzoxazole-2-yl}-2-methyl-2,3-dihydropyridazine-3-one (50 mg, 0.104 mmol) and 2-(2,6-dioxopiperidine-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (29 mg, 0.104 mmol) in DMF (2 mL) and DIPEA (36 μL, 0.208 mmol). The tubes were flushed with nitrogen and placed on a preheated 90°C heating block for 4 hours. The reaction mixture was retreated with 2-(2,6-dioxopiperidine-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (29 mg, 0.104 mmol) and DIPEA (36 μL, 0.208 mmol), and stirred at 90°C for a further 4 hours. The reaction mixture was cooled to room temperature, and the product was purified by low pH prep. The pure fractions were combined and freeze-dried overnight to obtain the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.29 (d, J = 2.9 Hz, 1H), 8.14 (d, J = 9.7 Hz, 1H), 7.75 (d, J = 8.9 Hz, 1H), 7.56 (dd, J = 8.4, 7.2 Hz, 1H), 7.52 - 7.45 (m, 2H), 7.42 (dd, J = 8.6, 2.9 Hz, 1H), 7.19 - 7.10 (m, 3H), 7.03 (d, J = 7.0 Hz, 1H), 6.60 (t, J = 5.8 Hz, 1H), 5.17 (s, 2H), 5.05 (dd, J = 12.8, 5.5 Hz, 1H), 4.20 - 4.14 (m, 2H), 3.80 (s, 3H), 3.78 - 3.74 (m, 2H), 3.66 - 3.56 (m, 6H), 3.46 (q, J = 5.5 Hz, 3H), 2.92 - 2.82 (m, 1H), 2.61 - 2.55 (m, 1H), 2.05 - 1.97 (m, 1H). Tr(METCR1603) = 4.21 min, (ES + ) (M+H)+ 738.4. 【0299】 The following compounds were prepared as described above. 【0300】 [Table 9] 【0301】 [Example 10] Scheme for Example 10 【0302】 [ka] 【0303】 Step 1: Methyl 5-{2-[2-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)ethoxy]ethoxy}pyridine-2-carboxylate A stirred solution of methyl 5-hydroxypyridine-2-carboxylate (500 mg, 3.26 mmol) and tert-butyl N-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}carbamate (895 mg, 3.59 mmol) in THF (20.0 mL) was cooled to 0°C and treated with triphenylphosphine (1.28 g, 4.90 mmol). The reaction mixture was stirred for 20 minutes, then treated with DIAD (0.96 μL, 4.90 mmol) added dropwise for 10 minutes. The mixture was stirred at 0°C for a further 30 minutes, then at room temperature overnight. Triphenylphosphine (428 mg, 1.63 mmol) was added, and the reaction mixture was stirred for 20 minutes, then treated with DIAD (0.32 mL, 1.63 mmol) added dropwise for 10 minutes. The mixture was stirred at 0°C for a further 30 minutes, then at room temperature for a further 6 hours. The reaction mixture was concentrated to dryness, and the crude product was suspended in water (50 mL). The aqueous substance was extracted with toluene (2 × 50 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and evaporated under reduced pressure to obtain a brown oily substance, which was purified by FCC (silica, heptane 10-45% toluene, followed by DCM 1-8% MeOH) to obtain the title compound. 1H NMR (250 MHz, chloroform-d) δ 8.42 (d, J = 2.8 Hz, 1H), 8.10 (d, J = 8.7 Hz, 1H), 7.29 (dd, J = 8.8, 3.0 Hz, 1H), 4.95 (s, 1H), 4.30 - 4.21 (m, 2H), 3.98 (s, 3H), 3.94 - 3.86 (m, 2H), 3.71 (dd, J = 5.8, 2.7 Hz, 2H), 3.64 (dd, J = 5.9, 2.8 Hz, 2H), 3.54 (t, J = 5.2 Hz, 2H), 3.37 - 3.25 (m, 2H), 1.43 (s, 9H). Tr (METCR1410 General 2 minutes) = 1.00 minutes, (ES + ) [M+H] + 385. 【0304】 Step 2: 5-{2-[2-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)ethoxy]ethoxy}pyridine-2-carboxylic acid A solution of methyl 5-{2-[2-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)ethoxy]ethoxy}pyridine-2-carboxylate (81%, 260 mg, 0.55 mmol) in THF (5 mL) and MeOH (5 mL) was mixed with 1 M NaOH (aq) (1.37 ml, 1.37 mmol) at room temperature, and the reaction mixture was stirred for 3 hours. The solvent was removed under vacuum, the aqueous phase was acidified with 1 M HCl, and the pH was adjusted to 2-3 at 0°C. The aqueous phase was extracted with DCM (3 × 15 mL). The combined organic layers were dried over Na₂SO₄, filtered, and evaporated under reduced pressure to obtain the title compound. Tr (METCR1410 General 2 min) = 0.92 min, (ES + ) [M+H] + 371. 【0305】 Step 3: tert-butyl N-[2-(2-{2-[(6-{[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazole-5-yl]carbamoyl}pyridine-3-yl)oxy]ethoxy}ethoxy)ethyl]carbamate A stirring solution of 5-{2-[2-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)ethoxy]ethoxy}pyridine-2-carboxylic acid (90 mg, 0.21 mmol) and HATU (94 mg, 0.25 mmol) in DMF (2.5 mL) was stirred under nitrogen at 0°C, and treated with dropwise addition of DIPEA (0.079 mL, 0.45 mmol). The reaction mixture was stirred at 0°C for 15 minutes, and then treated with 6-(5-amino-1,3-benzoxazole-2-yl)-2-methyl-2,3-dihydropyridazine-3-one (50 mg, 0.21 mmol). The resulting mixture was stirred at 0°C for 1 hour, and then stirred at room temperature for 4 hours. The reaction mixture was then subjected to direct high-pH prep-HPLC in two separate fractions. The pure fractions were combined, and the solvent was removed under vacuum. The obtained solid was dried overnight in a high-vacuum oven at 40°C to obtain the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 2.9 Hz, 1H), 8.18 (d, J = 9.7 Hz, 1H), 8.15 (d, J = 8.7 Hz, 1H), 7.99 (dd, J = 8.9, 2.1 Hz, 1H), 7.82 (d, J = 8.9 Hz, 1H), 7.65 (dd, J = 8.8, 2.9 Hz, 1H), 7.15 (d, J = 9.7 Hz, 1H), 6.75 (s, 1H), 4.33 - 4.27 (m, 2H), 3.83 - 3.79 (m, 5H), 3.61 (dd, J = 5.9, 3.6 Hz, 2H), 3.53 (dd, J = 5.8, 3.6 Hz, 2H), 3.39 (t, J = 6.1 Hz, 2H), 3.07 (q, J = 5.8 Hz, 2H), 1.36 (s, 9H). Tr (METCR1410 General 2 minutes) = 1.13 minutes, (ES + ) [M+H] + 595. 【0306】 Step 4: 5-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}-N-[2-(1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)-1,3-benzoxazole-5-yl]pyridine-2-carboxamide 90 mg, 0.15 mmol of tert-butyl N-[2-(2-{2-[(6-{[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazole-5-yl]carbamoyl}pyridine-3-yl)oxy]ethoxy}ethoxy)ethyl]carbamate (90 mg, 0.15 mmol) was dissolved in dioxane (4.0 mL), and 4 M HCl in dioxane (0.38 mL, 1.51 mmol) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 3 hours, and then left to stand overnight at room temperature. The solvent was removed under vacuum, and the residue was dissolved in water (15 mL) and basicized with a saturated solution of NaHCO3 (aq). The aqueous phase was extracted with a mixture of DCM-MeOH (5:1, 2 × 15 mL), followed by extraction with a solution of IPA-CHCl3 (4:1, 2 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure to obtain the title compound, which was used in the next step without purification. Tr (METCR1410 General 2 min) = 0.90 min, (ES + ) [M+H] + 495. 【0307】 Step 5 (5-{2-[2-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}ethoxy)ethoxy]ethoxy}-N-[2-(1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)-1,3-benzoxazole-5-yl]pyridine-2-carboxamide The sealed tubes were packed with 5-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}-N-[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazole-5-yl]pyridine-2-carboxamide (70 mg, 0.14 mmol) and 2-(2,6-dioxopiperidine-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (38.7 mg, 0.14 mmol) in DMF (2 mL) and DIPEA (36 mg, 0.28 mmol). The tubes were flushed with nitrogen and placed on a preheated 90°C heating block for 8 hours. The reaction mixture was cooled to room temperature and subjected to direct low pH-prep HPLC in two parts. The pure fractions were combined, and the solvent was removed by freeze-drying to obtain the title compound. 1 H NMR (500 MHz, DMSO-d6) 11.08 (s, 1H), 10.69 (s, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.39 (d, J = 2.9 Hz, 1H), 8.18 (d, J = 9.7 Hz, 1H), 8.13 (d, J = 8.7 Hz, 1H), 7.98 (dd, J = 8.9, 2.1 Hz, 1H), 7.82 (d, J = 8.9 Hz, 1H), 7.61 (dd, J = 8.8, 2.9 Hz, 1H), 7.57 (dd, J = 8.5, 7.2 Hz, 1H), 7.17 - 7.11 (m, 2H), 7.02 (d, J = 7.0 Hz, 1H), 6.60 (t, J = 5.8 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.30 - 4.25 (m, 2H), 3.84 - 3.79 (m, 5H), 3.67 - 3.58 (m, 6H), 3.50 - 3.44 (m, 2H), 2.92 - 2.82 (m, 1H), 2.60 - 2.53 (m, 2H), 2.05 - 1.98 (m, 1H). Tr(METCR1603 High pH 7min)= 3.9min, (ES+) (M+H)+ 751. 【0308】 The following compounds were prepared as described above. 【0309】 [Table 10] TIFF0007872824000065.tif214170TIFF0007872824000066.tif81168 【0310】 [Example 11] Scheme for Example 11 【0311】 [ka] 【0312】 Step 1: A mixture of 6-methoxybenzo[d]thiazole-2-amine (15.00 g, 83.00 mmol) and ethyl 3-bromo-2-oxopropanoate (10.5 mL, 16.3 g, 84.0 mmol) in 1,4-dioxane (150 mL) was heated at 90°C for 14 hours. After this, another portion of ethyl 3-bromo-2-oxopropanoate (2.5 mL, 3.9 g, 20 mmol) was added and heating was continued for a further 24 hours. Volatile substances were then removed under reduced pressure, and the resulting residue was treated with saturated sodium bicarbonate (200 mL) and ethyl acetate (300 mL). The mixture was stirred at 50°C for 1 hour, cooled to room temperature, and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, and filtered. The resulting ethyl acetate solution was treated with silica gel (100 mL), concentrated under reduced pressure, and purified by chromatography (silica gel, heptane to ethyl acetate, gradient elution) to obtain two product fractions. The cleaner fraction was ground with 95:5 heptane / ethyl acetate and filtered to obtain the product. The less clean fraction was dissolved in ethyl acetate (800 mL), the solution was washed with 0.1 N HCl (3 × 100 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the product was obtained. 1H NMR (500 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.09 (d, J = 9.0 Hz, 1H), 7.70 (d, J = 2.5 Hz, 1H), 7.16 (dd, J = 8.8, 3.0 Hz, 1H), 4.29 (q, J = 7.5 Hz, 2H), 3.84 (s, 3H), 1.31 (t, J = 7.0 Hz, 3H). 【0313】 Step 2: (7-Methoxybenzo[d]imidazo[2,1-b]thiazole-2-yl)methanol A 1 M solution of lithium aluminum hydride in THF (6.15 mL, 6.15 mmol) was added dropwise over 10 minutes to a solution of ethyl 7-methoxybenzo[d]imidazo[2,1-b]thiazole-2-carboxylate (2.00 g, 7.24 mmol) in THF (118 mL) cooled to -78°C. After the addition was complete, the suspension was warmed. When the mixture reached 0°C, it became clear, and TLC analysis indicated the completion of the consumption of the starting material. The solution was carefully poured into saturated ammonium chloride (150 mL) and filtered through diatomaceous earth. The filter cake was rinsed with ethyl acetate (3 × 75 mL) and the filtrate layer was separated. The aqueous layer was extracted with ethyl acetate (3 × 35 mL), the organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to chromatography (silica gel, ethyl acetate, 95:5 ethyl acetate / methanol, gradient elution) to obtain (7-methoxybenzo[d]imidazo[2,1-b]thiazole-2-yl)methanol. 1 H NMR (500 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 2.5 Hz, 1H), 7.10 (dd, J = 9.0, 2.5 Hz, 1H), 5.10 (t, J = 5.5 Hz, 1H), 4.47 (dd, J = 5.8, 1.0 Hz, 2H), 3.82 (s, 3H). 【0314】 Step 3: (7-Methoxybenzo[d]imidazo[2,1-b]thiazole-2-yl)pentaen-4-carbaldehyde (7-methoxybenzo[d]imidazo[2,1-b]thiazole-2-yl)methanol (80 mg, 0.31 mmol) was dissolved in dichloromethane (5 mL) and treated with des-martin periodinane (156 mg, 0.37 mmol). The mixture was stirred at room temperature for 64 hours. The reaction product was then quenched by adding saturated aqueous Na2S2O3 (2 mL) and saturated aqueous NaHCO3 (2 mL). The mixture was stirred for 5 minutes to induce dissolution of most of the precipitate. The mixture was diluted with water (10 mL) and dichloromethane (10 mL). The layers were separated, and the aqueous substance was further extracted with dichloromethane (2 × 10 mL). The combined organic extract was washed with brine (10 mL), dehydrated (MgSO4), filtered, concentrated, and the title compound was obtained. 1 H NMR (500 MHz, DMSO-d6) δ 9.83 (s, 1H), 9.06 (s, 1H), 8.08 (d, J = 8.9 Hz, 1H), 7.72 (d, J = 2.5 Hz, 1H), 7.18 (dd, J = 8.9, 2.5 Hz, 1H), 3.85 (s, 3H). Tr(METCR1673) = 1.10 min, (ES + ) (M+H) + 233. 【0315】 Step 4: 2-(7-methoxybenzo[d]imidazo[2,1-b]thiazole-2-yl)-3-(methyl-amino)imidazo-[1,2-a]pyridine-7-carbonitrile (7-Methoxybenzo[d]imidazo[2,1-b]thiazole-2-yl)pentaen-4-carbaldehyde (65 mg, 0.28 mmol) and 2-aminoisonicotinonitrile (33 mg, 0.28 mmol) were suspended in methanol (5 mL). AcOH (0.5 mL) and methyl isocyanide (22 μl, 0.42 mmol) were added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered, and the collected solid was dried under suction to obtain the title compound. 1H NMR (500 MHz, DMSO) 8.96 (s, 1H), 8.71 (s, 1H), 8.35 (d, J = 7.1 Hz, 1H), 8.15 (s, 1H), 8.05 (d, J = 8.9 Hz, 1H), 7.70 (d, J = 2.5 Hz, 1H), 7.16 (dd, J = 8.9, 2.5 Hz, 1H), 7.11 (dd, J = 7.1, 1.6 Hz, 1H), 5.63 (q, J = 5.8 Hz, 1H), 3.84 (s, 3H), 2.90 (d, J = 5.9 Hz, 3H). Tr(MET-uHPLC-AB-101)= 3.12 min, (ES + ) (M+H) + 375. 【0316】 Step 5: 2-(7-hydroxybenzo[d]imidazo[2,1-b]thiazole-2-yl)-3-(methylamino)-imidazo-[1,2-a]pyridine-7-carbonitrile A 1 M solution of boron tribromide in dichloromethane (8.2 mL, 8.2 mmol) was added dropwise to a suspension of 2-(7-methoxybenzo[d]imidazo[2,1-b]thiazole-2-yl)-3-(methyl-amino)imidazo-[1,2-a]pyridine-7-carbonitrile (0.601 g, 1.63 mmol, prepared from (7-methoxybenzo[d]imidazo[2,1-b]thiazole-2-yl)methanol by a method known in the art) in dichloromethane (80 mL) cooled to -78°C. The mixture was warmed to room temperature and stirred for 18 hours. After this, the crude product mixture was gradually added to a vigorously stirred saturated sodium bicarbonate solution (400 mL). Solid sodium bicarbonate was added periodically to maintain a pH of approximately 8. After the addition was complete, the crude product was filtered off as an orange solid. The filtrate was extracted with ethyl acetate (5 × 100 mL), the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was combined with the isolated solid product, and the whole was heated to 50°C in a mixture of methanol (100 mL) and acetonitrile (50 mL). Silica gel (75 mL) was added, the mixture was concentrated to dryness, dried under high vacuum, and subjected to chromatography (silica gel, dichloromethane, 91:9 dichloromethane / methanol, gradient elution) to obtain 2-(7-hydroxybenzo[d]imidazo[2,1-b]thiazole-2-yl)-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile. 1 H NMR (500 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.66 (s, 1H), 8.35 (d, J = 7.5 Hz, 1H), 8.14 (s, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.11 (dd, J = 7.0, 1.5 Hz, 1H), 6.96 (dd, J = 8.8, 2.5 Hz, 1H), 5.65 (q, J = 6.0 Hz, 1H), 2.89 (d, J = 6.0 Hz, 3H). 【0317】 Step 6: tert-butyl14-((2-(7-cyano-3-(methylamino)imidazo[1,2-a]pyridine-2-yl)benzo[d]imidazo[2,1-b]thiazole-7-yl)oxy)-3,6,9,12-tetraoxatetradecane-1-oate 2-(tributyl-15-phosphanylidene)acetonitrile (0.290 mL, 0.267 g, 1.11 mmol) was added to a suspension of 2-(7-hydroxybenzo[d]imidazo[2,1-b]thiazole-2-yl)-3-(methylamino)-imidazo[1,2-a]pyridine-7-carbonitrile (0.184 g, 0.511 mmol) and tert-butyl 14-hydroxy-3,6,9,12-tetraoxatetradecane-1-oate (0.317 g, 1.03 mmol) in toluene (10 mL), and the mixture was heated at 100°C for 6 hours. After that, the mixture was cooled and concentrated under reduced pressure. The resulting residue was adsorbed onto silica gel and subjected to chromatography (silica gel, ethyl acetate to 98:2 ethyl acetate / methanol, gradient elution). The product fractions were combined and subjected to chromatography again (silica gel, dichloromethane, 96:4 dichloromethane / methanol, gradient elution) to obtain tert-butyl14-((2-(7-cyano-3-(methylamino)imidazo[1,2-a]pyridine-2-yl)benzo[d]imidazo[2,1-b]thiazole-7-yl)oxy)-3,6,9,12-tetraoxatetradecane-1-oate. 1H NMR (500 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.35 (dd, J = 7.0, 1.0 Hz, 1H), 8.16-8.15 (m, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 2.5 Hz, 1H), 7.18 (dd, J = 8.5, 2.5 Hz, 1H), 7.12 (dd, J = 7.3, 2.0 Hz, 1H), 5.64 (q, J = 6.0 Hz, 1H), 4.19-4.17 (m, 2H), 3.97 (s, 2H), 3.80-3.78 (m, 2H), 3.62-3.60 (m, 2H), 3.57-3.52 (m, 10H), 2.90 (d, J = 5.5 Hz, 3H), 1.40 (s, 9H); MS (ESI) m / z 651 [M + H] + . 【0318】 Step 7: (2S,4R)-1-((S)-2-(tert-butyl)-17-((2-(7-cyano-3-(methylamino)-imidazo[1,2-a]pyridine-2-yl)benzo[d]imidazo[2,1-b]thiazole-7-yl)oxy)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecane-1-oil)-4-hydroxy-N-(4-(4-methylthiazole-5-yl)benzyl)-pyrrolidine-2-carboxamide Trifluoroacetic acid (0.50 mL, 0.75 g, 35 mmol) was added dropwise to a solution of tert-butyl 14-((2-(7-cyano-3-(methylamino)imidazo[1,2-a]pyridine-2-yl)benzo[d]imidazo[2,1-b]thiazole-7-yl)oxy)-3,6,9,12-tetraoxatetradecane-1-oate (0.120 g, 0.184 mmol) in dichloromethane (8 mL), and the mixture was stirred at room temperature. After 4 hours, TLC analysis showed an incomplete reaction, so an additional portion of trifluoroacetic acid (0.50 mL, 0.75 g, 35 mmol) was added, and the reaction was continued for another 2 hours. After this, volatile substances were removed under reduced pressure. The resulting residue was azeotropically reacted with dichloromethane (2 × 20 mL), then toluene (2 × 20 mL), and then dichloromethane again (2 × 20 mL) to obtain crude 14-((2-(7-cyano-3-(methylamino)imidazo[1,2-a]pyridine-2-yl)benzo[d]imidazo[2,1-b]thiazole-7-yl)oxy)-3,6,9,12-tetraoxatetradecane-1-euic acid. 【0319】 Crude N,N-dimethylformamide (8 mL) contains 14-((2-(7-cyano-3-(methylamino)imidazo[1,2-a]pyridine-2-yl)benzo-[d]imidazo[2,1-b]thiazole-7-yl)oxy)-3,6,9,12-tetraoxatetradecane-1-euic acid (0.184 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methyl-thiazole-5-yl)benzyl)pyrrolidine-2-carboxamide (0.0840 g, 0.195 mmol, Galdeano et al., J. Med. Chem.). To a solution of (see Vol. 57, pp. 8657-8663, 2014), N,N-diisopropylethylamine (0.128 mL, 0.0950 g, 0.733 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. HATU (0.084 g, 0.23 mmol) was then added, and the mixture was stirred at room temperature for 30 minutes. After this, water (15 mL) was added, the aqueous layer was saturated with sodium chloride, and extracted with ethyl acetate (6 × 50 mL). The organic layers were combined, washed with brine (4 × 30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to chromatography (silica gel, dichloromethane, 92:8 dichloromethane / methanol, gradient elution) to obtain the title compound. This material was dissolved in dichloromethane (3 mL) and precipitated by addition to heptane (25 mL). The resulting solid was filtered and freeze-dried in 50:50 acetonitrile / water (9 mL) to obtain the title compound. 1¹H NMR (500 MHz, DMSO-d6, observed as a 94:6 mixture of rotational isomers; shows the chemical shift of the major isomer) δ 8.97 (s, 1H), 8.72 (s, 1H), 8.60 (t, J = 6.0 Hz, 1H), 8.35 (dd, J = 7.0, 0.5 Hz, 1H), 8.15 (br s, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.69 (d, J = 2.5 Hz, 1H), 7.42-7.37 (m, 5H), 7.16 (dd, J = 9.0, 2.5 Hz, 1H), 7.11 (dd, J = 7.0, 1.5 Hz, 1H), 5.64 (q, J = 5.5 Hz, 1H), 5.15 (d, J = 3.6 Hz, 1H), 4.56 (d, J = 9.5 Hz, 1H), 4.46-4.35 (m, 3H), 4.24 (dd, J = 16.0, 5.5 Hz, 1H), 4.17-4.15 (m, 2H), 3.96 (s, 2H), 3.77-3.75 (m, 2H), 3.67 (dd, J = 10.5, 3.5 Hz, 1H), 3.61-3.52 (m, 13H), 2.89 (d, J = 6.0 Hz, 3H), 2.43 (s, 3H), 2.07-2.04 (m, 1H), 1.93-1.87 (m, 1H), 0.94 (s, 9H); MS (ESI) m / z 1007 [M + H] + ; HPLC: Method 1, t R = 6.01 minutes. 【0320】 The following compounds were prepared as described above. 【0321】 [Table 11] TIFF0007872824000069.tif76161 【0322】 [Example 12] Scheme for Example 12 【0323】 [ka] 【0324】 Step 1: 2-(2-(((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide)methyl)-5-(4-methylthiazole-5-yl)phenoxy)-ethyl 4-methylbenzenesulfonate A mixture of (2S,4R)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazole-5-yl)benzyl)-1-((S)-3-methyl-2-(1-oxoisoindorin-2-yl)butanoyl)pyrrolidine-2-carboxamide (0.150 g, 0.273 mmol), ethane-1,2-diylbis(4-methylbenzenesulfonate) (0.506 g, 1.37 mmol), and cesium carbonate (0.136 g, 0.417 mmol) in acetonitrile (10 mL) was heated at 60 °C for 2 hours. After this, the mixture was cooled to room temperature and filtered through glass frit. The filtered cake was rinsed with dichloromethane (3 × 5 mL) and ethyl acetate (3 × 5 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to chromatography (silica gel, dichloromethane, 95:5 dichloromethane / methanol, gradient elution) to obtain the title compound. 1¹H NMR (500 MHz, DMSO-d⁶, mixture of reductants, chemical analysis of the main reductant): δ 8.98 (s, 1H), 8.36 (t, J = 6.0 Hz, 1H), 7.82–7.80 (m, 2H), 7.72 (d, J = 7.5 Hz, 1H), 7.64–7.60 (m, 2H), 7.51 (ddd, J = 7.7, 5.8, 2.5 Hz, 1H), 7.46–7.44 (m, 2H), 7.32 (d, J = 8.0 Hz, 1H), 7.00 (dd, J = 8.0, 1.5 Hz, 1H). 6.93 (d, J = 1.5 Hz, 1H), 5.09 (d, J = 4.0 Hz, 1H), 4.72 (d, J = 11.0 Hz, 1H), 4.56 (d, J = 18.0 Hz, 1H), 4.47 (d, J = 18.0 Hz, 1H), 4.42 (t, J = 8.0 Hz, 1H), 4.39-4.34 (m, 3H), 4.27-4.25 (m, 2H), 4.14-4.05 (m, 2H), 3.79 (dd, J = 10.8, 4.5 Hz, 1H), 3.70 (d, J = 10.5 Hz, 1H), 2.44 (s, 3H), 2.36 (s, 3H), 2.34-2.32 (m, 1H), 2.09-2.05 (m, 1H), 1.95 (ddd, J = 12.8, 8.0, 5.0 Hz, 1H), 0.97 (d, J = 6.5 Hz, 3H), 0.74 (d, J = 6.5 Hz, 3H); MS (ESI) m / z 769 [M + Na] + 747 [M + H] + . 【0325】 Step 2: (2S,4R)-N-(2-(2-((2-(7-cyano-3-(methylamino)imidazo[1,2-a]pyridine-2-yl)benzo[d]imidazo[2,1-b]thiazole-7-yl)oxy)ethoxy)-4-(4-methylthiazole-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindorin-2-yl)butanoyl)pyrrolidine-2-carboxamide A mixture of 2-(2-(((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-pyrrolidine-2-carboxamide)methyl)-5-(4-methylthiazole-5-yl)phenoxy)ethyl 4-methylbenzenesulfonate (0.112 g, 0.150 mmol), 2-(7-hydroxybenzo[d]imidazo[2,1-b]thiazole-2-yl)-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile (0.056 g, 0.16 mmol), and cesium carbonate (0.099 g, 0.30 mmol) in N,N-dimethylformamide (8 mL) was heated at 60°C for 2 hours. The mixture was then cooled to room temperature, and ethyl acetate (15 mL), water (15 mL), and brine (15 mL) were added. The resulting orange-brown precipitate was removed by filtration, and the filtrate layer was separated. The aqueous layer was extracted with ethyl acetate (4 × 20 mL), the organic layers were combined, washed with brine (4 × 20 mL), dried over sodium sulfate, and filtered. The solid collected before extraction was dissolved in dichloromethane / methanol and added to the ethyl acetate extract, after which the whole was concentrated under reduced pressure. The resulting residue was adsorbed onto silica gel and subjected to chromatography (silica gel, dichloromethane to 93:7 dichloromethane / methanol, gradient elution) to obtain the title compound. The obtained product was dissolved in a mixture of methylene chloride and methanol (92:8, 4.0 mL), and the solution was added dropwise to a stirred mixture of heptane and ethyl acetate (95:5, 20 mL). The suspension was stirred at room temperature for approximately 30 minutes and filtered. The filtered cake was washed with a mixture of heptane and ethyl acetate (95:5, 2 × 3 mL), dried under reduced pressure, freeze-dried in 2:1 acetonitrile / water (10 mL), and dried in vacuum at 55°C for 2 hours to obtain the title compound. 1¹H NMR (500 MHz, DMSO-d6, mixture of rotational isomers, chemical shift of the main rotational isomer is indicated) δ 8.99 (s, 1H), 8.72 (s, 1H), 8.37-8.34 (m, 2H), 8.14 (s, 1H), 8.05 (d, J = 9.0 Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.60 (d, J = 4.0 Hz, 2H), 7.50-7.47 (m, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.24 (dd, J = 9.0, 2.5 Hz, 1H), 7.12-7.10 (m, 2H), 7.04 (dd, J = 8.0, 1.5 Hz, 1H), 5.64 (q, J = 6.0 Hz, 1H), 5.06 (d, J = 4.0 Hz, 1H), 4.70 (d, J = 11.0 Hz, 1H), 4.55-4.38 (m, 7H), 4.31-4.21 (m, 3H), 3.77 (dd, J = 10.5, 4.5 Hz, 1H), 3.67 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 3.0 Hz, 3H), 2.48 (s, 3H), 2.34-2.26 (m, 1H), 2.04-2.00 (m, 1H), 1.92-1.87 (m, 1H), 0.94 (d, J = 6.5 Hz, 3H), 0.71 (d, J = 6.5 Hz, 3H); MS (ESI) m / z 957 [M + Na] + HPLC t R = 6.41 minutes. 【0326】 The following compounds were prepared as described above. 【0327】 [Table 12] TIFF0007872824000072.tif47164 【0328】 [Example 13] Scheme for Example 13 【0329】 [ka] 【0330】 Step 1: N-(2,5-dihydroxyphenyl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide EDC (0.774 g, 4.03 mmol) was added to a mixture of 2-aminobenzene-1,4-diol hydrochloride (0.500 g, 3.09 mmol) and 1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (0.526 g, 3.41 mmol) in anhydrous pyridine (4 mL), and the reaction mixture was stirred at room temperature for 16 hours. After this, the solvent was removed under reduced pressure, and the resulting residue was pulverized with a 2:2:1 methylene chloride / ethyl acetate / methanol mixture (20 mL). The solid product was filtered and rinsed with cold methanol (3 × 5 mL) to obtain the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 9.49 (s, 1H), 9.46 (s, 1H), 8.85 (s, 1H), 7.97 (d, J = 9.5 Hz, 1H), 7.74 (d, J = 3.0 Hz, 1H), 7.09 (d, J = 9.5 MS (ESI) m / z 262 [M + H] + . 【0331】 Step 2: 6-(5-hydroxybenzo[d]oxazol-2-yl)-2-methylpyridazine-3(2H)-one A suspension of N-(2,5-dihydroxyphenyl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (0.150 g, 0.574 mmol) in glacial acetic acid (2.5 mL) was heated at 200 °C for 3.5 hours under microwave irradiation. The solvent was then removed under reduced pressure, and the resulting residue was pulverized with a 2:2:1 methylene chloride / ethyl acetate / methanol mixture (10 mL) to obtain the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.12 (d, J = 10.0 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.14-7.12 (m, 2H), 6.92 (dd, J = 9.0, 2.5 Hz, 1H), 3.79 (s, 3H); MS (ESI) m / z 244 [M + H] + . 【0332】 Step 3: 6-(5-((5-(allyloxy)pyridin-2-yl)methoxy)benzo[d]oxazol-2-yl)-2-methylpyridazine-3(2H)-one Sodium hydride (60% dispersion in mineral oil, 0.280 g, 6.99 mmol) was added to a mixture of 6-(5-hydroxybenzo[d]oxazole-2-yl)-2-methylpyridazine-3(2H)-one (0.567 g, 2.33 mmol), 5-(allyloxy)-2-(chloromethyl)pyridine (0.856 g, 4.66 mmol), and potassium iodide (0.387 g, 2.33 mmol) in anhydrous N,N-dimethylacetamide (16 mL). The resulting reaction mixture was stirred at room temperature for 10 minutes, then heated at 80°C for 2 hours. After this, the reaction mixture was cooled to room temperature and quenched with water (100 mL). The product was extracted with methylene chloride (2 × 100 mL), the combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, methylene chloride to 95:5 methylene chloride / methanol, gradient elution). The resulting product was purified again by chromatography (silica gel, methylene chloride to ethyl acetate, gradient elution) to obtain the title compound. 1H NMR (500 MHz, CDCl3) δ 8.32 (d, J = 2.8 Hz, 1H), 8.12 (d, J = 9.7 Hz, 1H), 7.55-7.46 (m, 2H), 7.35-7.29 (m, 2H), 7.14 (dd, J = 8.9, 2.5 Hz, 1H), 7.07 (d, J = 9.7 Hz, 1H), 6.11-5.97 (m, 1H), 5.48-5.33 (m, 2H), 5.25 (s, 2H), 4.61 (d, J = 5.3 Hz, 2H), 3.96 (s, 3H). 【0333】 Step 4: 6-(5-((5-hydroxypyridine-2-yl)methoxy)benzo[d]oxazol-2-yl)-2-methylpyridazine-3(2H)-one A mixture of 6-(5-((5-(allyloxy)pyridine-2-yl)methoxy)benzo[d]oxazole-2-yl)-2-methylpyridazine-3(2H)-one (0.295 g, 0.756 mmol) and 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (0.118 g, 0.756 mmol) in anhydrous methanol (30 mL) was purged with nitrogen for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.021 g, 0.019 mmol) was added, the mixture was purged with nitrogen for an additional 5 minutes, and then heated at 50°C for 2 hours. Subsequently, the solid product was filtered, rinsed with methanol, and adsorbed onto silica gel. It was then purified by chromatography (silica gel, methylene chloride, 90:10 methylene chloride / methanol, gradient elution) to obtain 6-(5-((5-hydroxypyridine-2-yl)methoxy)benzo[d]oxazole-2-yl)-2-methylpyridazine-3(2H)-one. The isolated product was recrystallized from DMSO and freeze-dried to obtain a clean product. 1H NMR (500 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.14-8.12 (m, 2H), 7.74 (d, J = 8.9 Hz, 1H), 7.47 (d, J = 2.5 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 8.4, 2.9 Hz, 1H), 7.16-7.12 (m, 2H), 5.12 (s, 2H), 3.80 (s, 3H); MS (ESI) m / z 351 [M + H] + HPLC: t R = 7.84 minutes. 【0334】 Step 5: (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butane-oil)-N-(2-(2-((6-(((2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzo[d]oxazole-5-yl)oxy)methyl)pyridine-3-yl)oxy)ethoxy)-4-(4-methylthiazole-5-yl)benzyl)pyrrolidine-2-carboxamide Cesium carbonate (0.086 g, 0.27 mmol) was added to a suspension of 2-(2-(((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide)-methyl)-5-(4-methylthiazole-5-yl)phenoxy)ethyl 4-methylbenzenesulfonate (0.099 g, 0.13 mmol) and 6-(5-((5-hydroxypyridine-2-yl)methoxy)benzo[d]oxazole-2-yl)-2-methylpyridazine-3(2H)-one (0.056 g, 0.16 mmol) in N,N-dimethylformamide (15 mL) in a microwave reaction tube. The tube was sealed and placed in a preheated aluminum block, and the mixture was stirred at 60°C for 4.5 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was adsorbed onto silica gel and purified by column chromatography (silica gel, dichloromethane to 86:14 dichloromethane / methanol, gradient elution) to obtain (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(2-(2-((6-(((2-(1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)benzo[d]oxazole-5-yl)oxy)methyl)pyridine-3-yl)oxy)ethoxy)-4-(4-methylthiazole-5-yl)benzyl)pyrrolidine-2-carboxamide. This material was combined with another lot and purified by column chromatography (silica gel, chloromethane to 86:14 dichloromethane / methanol, gradient elution). The obtained product was dissolved in a 96:4 dichloromethane / methanol (1 mL) solution and added to a stirred 88:12 heptane / ethyl acetate (13 mL) solution. The suspension was stirred for 5 minutes, allowed to stand for 20 minutes, and filtered. The filtered cake was washed with 88:12 heptane / ethyl acetate (2 × 5 mL), then dissolved in a 1:1 acetonitrile / water (17 mL) solution, lyophilized, and the title compound was obtained. 1¹H NMR (500 MHz, DMSO-d⁶; ⁻¹⁰ NMR (500 MHz, DMSO-d⁶; ⁻¹⁰ NMR data) δ 9.00 (s, 1H), 8.38 (t, J = 1.5 Hz, 1H), 8.35 (t, J = 6.0 Hz, 1H), 8.13 (d, J = 9.5 Hz, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.62–7.60 (m, 2H), 7.54–7.53 (m, 2H), 7.51–7.48 (m, 2H), 7.35 (d, J = 7.5 Hz, 1H) 7.17 (dd, J = 9.0, 2.5 Hz, 1H), 7.14 (d, J = 9.5 Hz, 1H), 7.12 (d, J = 1.5 Hz, 1H), 7.03 (dd, J = 7.5, 1.5 Hz, 1H), 5.20 (s, 2H), 5.07 (d, J = 4.0 Hz, 1H), 4.70 (d, J = 11.0 Hz, 1H), 4.54 (d, J = 18.0 Hz, 1H), 4.50-4.48 (m, 2H), 4.46-4.41 (m, 3H), 4.39 (d, J = 8.0 Hz, 1H), 4.32-4.19 (m, 3H), 3.79 (s, 3H), 3.75 (dd, J = 10.5, 4.5 Hz, 1H), 3.68 (d, J = 11.0 Hz, 1H), 2.48 (s, 3H), 2.34-2.26 (m, 1H), 2.04-2.00 (m, 1H), 1.92-1.87 (m, 1H), 0.94 (d, J = 6.5 Hz, 3H), 0.71 (d, J = 6.5 Hz, 3H); MS (ESI) m / z 947 [M + Na] + HPLC: Method 1, t R = 5.71 points. 【0335】 The following compounds are the same as those mentioned above. 【0336】 Table 13 【0337】 [Example 14] Scheme for Example 14 【0338】 [ka] 【0339】 Step 1: (5-(allyloxy)pyridine-2-yl)methanol A solution of potassium carbonate (1.65 g, 11.9 mmol) in water (4 mL) was added dropwise over 15 minutes to a mixture of 6-(hydroxymethyl)pyridine-3-ol (1.00 g, 7.99 mmol) and allyl bromide (0.80 mL, 9.3 mmol) in anhydrous acetone (10 mL). The reaction mixture was heated in a sealed tube at 60°C for 2 hours. After this, the mixture was cooled to room temperature, and the product was extracted with MTBE (3 × 100 mL). The organic layers were combined, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound, which was used in the next step without further purification. 1 H NMR (500 MHz, DMSO-d6) δ 8.19 (dd, J = 2.5, 0.5 Hz, 1H), 7.49-7.35 (m, 2H), 6.07-5.99 (m, 1H), 5.40 (dq, J = 17.5, 1.5 Hz, 1H), 5.29-5.25 (m, 2H), 4.63 (dt, J = 5.0, 1.5 Hz, 2H), 4.48 (d, J = 5.5 Hz, 2H). 【0340】 Step 2: 5-(allyloxy)-2-(chloromethyl)pyridine Thionyl chloride (1.27 mL, 17.6 mmol) was added dropwise at 0°C to a solution of (5-(allyloxy)pyridine-2-yl)methanol (1.45 g, 8.78 mmol) in anhydrous methylene chloride (30 mL). The resulting mixture was stirred at 0°C for 30 minutes and at room temperature for 2 hours. The mixture was then concentrated under reduced pressure. The resulting residue was dissolved in methylene chloride (100 mL) and washed with saturated aqueous sodium bicarbonate (75 mL). The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 8.27 (d, J = 2.7 Hz, 1H), 7.50-7.40 (m, 2H), 6.11-5.98 (m, 1H), 5.41 (dq, J = 17.1, 2.5 Hz, 1H), 5.29 (dq, J = 17.5, 2.5 Hz, 1H), 4.73 (s, 2H), 4.67 (dt, J = 9.0, 2.5 Hz, 2H). 【0341】 Step 3: 5-((5-(allyloxy)pyridine-2-yl)methoxy)-2-methylbenzo[d]oxazole Sodium hydride (60% dispersion in mineral oil, 0.263 g, 6.57 mmol) was added to a solution of 5-(allyloxy)-2-(chloromethyl)pyridine (1.06 g, 4.73 mmol), 2-methylbenzo[d]-oxazole-5-ol (0.700 g, 4.69 mmol), and potassium iodide (0.156 g, 0.939 mmol) in N,N-dimethylacetamide (60 mL), and the mixture was stirred at room temperature for 7.75 hours. After this, the reaction mixture was cooled to 0°C in an ice / water bath and slowly treated with water (150 mL). The resulting mixture was poured into stirred water (500 mL), diluted with water to a total volume of 1 L, and stirred for 5 minutes. The resulting suspension was placed in an ice / water bath, left for 30 minutes, and filtered. The filtered cake was washed with water (2 × 20 mL), dried under vacuum, and the title compound was obtained. The filtrate from the above was extracted with ethyl acetate (4 × 100 mL), the combined organic layers were washed with water (2 × 100 mL) and brine (50 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, heptane to 60:40 heptane / ethyl acetate, gradient elution) to obtain the additional title compound. 1 H NMR (500 MHz, DMSO-d6) δ 8.30 (d, J = 3.0 Hz, 1H), 7.54 (d, J = 9.0 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.43 (dd, J = 8.5, 3.0 Hz, 1H), 7.29 (d, J = 2.5 Hz, 1H), 6.99 (dd, J = 9.0, 2.5 Hz, 1H), 6.08-6.01 (m, 1H), 5.41 (dq, J = 17.5, 1.5 Hz, 1H), 5.29 (dq, J = 10.5, 1.5 Hz, 1H), 5.13 (s, 2H), 4.66 (t, J = 1.5 Hz, 1H), 4.65 (t, J = 1.5 Hz, 1H), 2.57 (s, 3H). 【0342】 Step 4: 4-((5-(allyloxy)pyridine-2-yl)methoxy)-2-aminophenol 2M hydrochloric acid (5.5 mL, 11 mmol) was added at room temperature to a stirred solution of 5-((5-(allyl-oxy)pyridine-2-yl)methoxy)-2-methylbenzo[d]oxazole (0.538 g, 1.82 mmol) in ethanol (11 mL). The resulting suspension was placed in a preheated aluminum block and stirred at 105°C for 6 hours. The reaction mixture was then cooled to room temperature, and the ethanol was removed under reduced pressure. The resulting residue was partitioned between saturated aqueous sodium bicarbonate (100 mL) and dichloromethane (50 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.26 (dd, J = 2.5, 1.0 Hz, 1H), 7.41 (dd, J = 8.5, 2.5 Hz, 1H), 7.38 (dd, J = 8.5, 1.0 Hz, 1H), 6.50 (d, J = 8.5 Hz, 1H), 6.27 (d, J = 3.0 Hz, 1H), 6.09-6.00 (m, 2H), 5.41 (dq, J = 17.5, 1.5 Hz, 1H), 5.28 (dq, J = 10.5, 1.5 Hz, 1H), 4.90 (s, 2H), 4.65 (t, J = 1.5 Hz, 1H), 4.62 (t, J = 1.5 Hz, 1H), 4.54 (br s, 2H). 【0343】 Step 5: 5-((5-(allyloxy)pyridine-2-yl)methoxy)-2-(5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-yl)benzo[d]oxazole Dichlorodiphenoxymethane (0.3 g, 1.0 mmol) was added to a solution of 4-((5-(allyloxy)-pyridine-2-yl)methoxy)-2-aminophenol (0.27 g, 0.98 mmol), 5,6,7,8-tetrahydroimidazo-[1,2-a]pyrazine (0.1 g, 1.0 mmol), and triethylamine (0.1 mL, 1.0 mmol) in toluene (7.0 mL) and 1,2-dichloroethane (1.0 mL). The resulting reaction mixture was heated at 80 °C for 24 hours. The mixture was then slowly cooled to room temperature, diluted with dichloromethane (15 mL), and quenched with saturated sodium bicarbonate (15 mL). The mixture was vigorously stirred for 5 minutes to separate the phases, and the aqueous phase was extracted with dichloromethane (3 × 20 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under vacuum. The obtained residue was purified to the title compound by column chromatography (silica gel, dichloromethane, 90:10 dichloromethane / methanol, gradient elution). 1 H NMR (500 MHz, DMSO-d6) δ 8.29 (d, J = 3.0 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.42 (dd, J = 8.5, 3.0 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 7.15 (d, J = 1.5 Hz, 1H), 7.01 (d, J = 2.5 Hz, 1H), 6.91 (d, J = 1.0 Hz, 1H), 6.70 (dd, J = 9.0, 1.0 Hz, 1H), 6.08-6.00 (m, 1H), 5.41 (dq, J = 17.5, 1.5Hz, 1H), 5.28 (dq, J = 11.0, 2.0 Hz, 1H), 5.08 (s, 2H), 4.79 (s, 2H), 4.65 (dt, J = 5.5, 1.5 Hz, 2H), 4.15 (t, J = 5.5 Hz, 2H), 4.05 (t, J = 5.5Hz, 2H). Additionally, 5-((5-(allyloxy)pyridine-2-yl)methoxy)-2-phenoxybenzo[d]oxazole was isolated by chromatography. 1H NMR (500 MHz, DMSO-d6) δ 8.29 (dd, J = 2.0, 0.5 Hz, 1H), 7.53-7.46 (m, 6H), 7.41 (dd, J = 8.5, 2.5 Hz, 1H), 7.38-7.35 (m, 1H), 7.18 (d, J = 2.5 Hz, 1H), 6.93 (dd, J = 8.5, 2.5 Hz, 1H), 6.07-6.00 (m, 1H), 5.41 (dq, J = 17.5, 1.5 Hz, 1H), 5.28 (dq, J = 11.0, 2.0 Hz, 1H), 5.10 (s, 2H), 4.65 (dt, J = 5.5, 1.5 Hz, 2H). 【0344】 Step 6: 5-((5-(allyloxy)pyridine-2-yl)methoxy)-2-(5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-yl)benzo[d]oxazole Cesium carbonate (0.305 g, 0.935 mmol) was added to a solution of 5-((5-(allyloxy)-pyridine-2-yl)methoxy)-2-phenoxybenzo[d]oxazole (0.14 g, 0.37 mmol) and 5,6,7,8-tetra-hydroimidazo[1,2-a]pyrazine (0.115 g, 0.935 mmol) in N,N-dimethylformamide (15 mL), and the reaction mixture was heated at 50 °C for 24 hours. After that, the mixture was cooled to room temperature, quenched with water (30 mL), and extracted with ethyl acetate (3 × 50 mL). The combined organic phase was washed with brine (3 × 50 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by column chromatography (silica gel, dichloromethane to 90:10 dichloromethane / methanol, gradient elution) to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ 8.29 (d, J = 3.0 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.42 (dd, J = 8.5, 3.0 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 7.15 (d, J = 1.5 Hz, 1H), 7.01 (d, J = 2.5 Hz, 1H), 6.91 (d, J = 1.0 Hz, 1H), 6.70 (dd, J = 9.0, 1.0 Hz, 1H), 6.08-6.00 (m, 1H), 5.41 (dq, J = 17.5, 1.5Hz, 1H), 5.28 (dq, J = 11.0, 2.0 Hz, 1H), 5.08 (s, 2H), 4.79 (s, 2H), 4.65 (dt, J = 5.5, 1.5 Hz, 2H), 4.15 (t, J = 5.5 Hz, 2H), 4.05 (t, J = 5.5Hz, 2H). 【0345】 Step 7: 6-(((2-(5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-yl)benzo[d]oxazole-5-yl)oxy)methyl)pyridine-3-ol A mixture of 5-((5-(allyloxy)pyridine-2-yl)methoxy)-2-(5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-yl)benzo[d]oxazole (0.97 g, 2.4 mmol) and 1,3-dimethylbarbituric acid (0.45 g, 2.9 mmol) in anhydrous methanol (96 mL) was purged with argon for 30 minutes. Tetrakis-(triphenylphosphine)palladium(0) (0.14 g, 0.12 mmol) was added, and the mixture was stirred at 50°C for 1 hour. After that, the mixture was cooled to room temperature, diluted with water (100 mL), and extracted with dichloromethane (3 × 100 mL). The combined organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by column chromatography (silica gel, dichloromethane, 90:10 dichloromethane / methanol, gradient elution) to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.36-7.33 (m, 2H), 7.19-7.15 (m, 2H), 7.01 (d, J = 3.5 Hz, 1H), 6.91 (d, J = 1.0 Hz, 1H), 6.69 (dd, J = 8.5, 2.5 Hz, 1H), 5.02 (s, 2H), 4.79 (s, 2H), 4.15 (t, J = 5.5 Hz, 2H), 4.05 (t, J = 5.5 Hz, 2H). 【0346】 Step 8: 2-(2-(2-(2-((6-((((2-(5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-yl)benzo-[d]oxazole-5-yl)oxy)methyl)pyridine-3-yl)oxy)ethoxy)ethoxy)ethoxy)acetic acid Sodium hydride (60% dispersion in mineral oil, 0.040 g, 1.1 mmol) was added at 0°C to a solution of 6-(((2-(5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-yl)benzo[d]oxazole-5-yl)oxy)-methyl)pyridine-3-ol (0.2 g, 0.5 mmol) and tert-butyl 2-(2-(2-(2-((methylsulfonyl)oxy)-ethoxy)ethoxy)ethoxy)acetate (0.23 g, 0.66 mmol) in N,N-dimethylacetamide (9 mL). After 10 minutes, the mixture was heated at 50°C for 4.5 hours. The mixture was then quenched with water (20 mL) and extracted with ethyl acetate (2 × 50 mL). The aqueous phase was concentrated in a vacuum, and the resulting residue was adsorbed onto diatomaceous earth. The residue was then purified by reverse-phase chromatography (C18, 95:5 water / acetonitrile to acetonitrile gradient elution) to obtain the title compound. 1H NMR (500 MHz, CDCl3) δ 8.25 (d, J = 2.5 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 8.5, 3.0 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 7.05 (d, J = 1.0 Hz, 1H), 6.98 (d, J = 2.5 Hz, 1H), 6.87 (d, J = 1.0 Hz, 1H), 6.68 (dd, J = 8.5, 2.5 Hz, 1H), 5.07 (s, 2H), 4.91 (s, 2H), 4.15-4.09 (m, 6H), 3.81 (br s, 4H), 3.68-3.53 (m, 8H). 【0347】 Step 9: (2S,4R)-1-((S)-2-(tert-butyl)-14-((6-(((2-(5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-yl)benzo[d]oxazole-5-yl)oxy)methyl)pyridine-3-yl)oxy)-4-oxo-6,9,12-trioxa-3-azatetradecane-1-oil)-4-hydroxy-N-(4-(4-methylthiazole-5-yl)benzyl)-pyrrolidine-2-carboxamide HATU (0.058g, 0.15mmol) is added to 2-(2-(2-(2-((6-((((2-(5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-yl)benzo[d]oxazole-5-yl)oxy)methyl)pyridine-3-yl)oxy)ethoxy)-ethoxy)ethoxy)acetic acid (0.085g, 0.15mmol) in N,N-dimethylformamide. l) was added to a solution of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazole-5-yl)benzyl)pyrrolidine-2-carboxamide (0.060 g, 0.14 mmol) and N,N-diisopropylethylamine (0.146 mL, 0.836 mmol), and the mixture was stirred at room temperature for 30 minutes. Then, saturated sodium carbonate (20 mL) was added, and the mixture was extracted with ethyl acetate (3 × 40 mL). The combined organic phase was washed with brine (3 × 30 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by column chromatography (silica gel, dichloromethane to 90:10 dichloromethane / / 9:1 methanol / ammonium hydroxide, gradient elution), and the obtained product was freeze-dried in 1:1 water / acetonitrile to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.59 (t, J = 6.0 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.44-7.33 (m, 8H), 7.15 (d, J = 1.0 Hz, 1H), 7.01 (d, J = 2.5 Hz, 1H), 6.91 (d, J = 1.0 Hz, 1H), 6.69 (dd, J = 8.5, 2.5 Hz, 1H), 5.15 (d, J = 4.0 Hz, 1H), 5.07 (s, 2H), 4.79 (s, 2H), 4.56 (d, J = 9.5 Hz, 1H), 4.45-4.34 (m, 3H), 4.24 (dd, J = 16.0, 3.0 Hz, 1H), 4.16-4.14 (m, 4H), 4.04 (t, J = 5.5 Hz, 2H), 3.96 (s, 2H), 3.73-3.71 (m, 2H), 3.67-3.55 (m, 10H), 2.43 (s, 3H), 2.08-2.03 (m, 1H), 1.92-1.87 (m, 1H), 0.93 (s, 9H); MS (ESI) m / z 966 [M + H] + ; HPLC: Method 2, t R = 4.80 minutes. 【0348】 The following compounds were prepared as described above. 【0349】 [Table 14] 【0350】 [Example 15] Scheme for Example 15 【0351】 [ka] 【0352】 Step 1: tert-butyl 4-(5-((5-(allyloxy)pyridine-2-yl)methoxy)benzo[d]oxazole-2-yl)piperazine-1-carboxylate Tetramethoxymethane (0.42 mL, 3.2 mmol) was added to a solution of 4-((5-(allyloxy)-pyridine-2-yl)methoxy)-2-aminophenol (0.426 g, 1.56 mmol), tert-butylpiperazine-1-carboxylate (0.584 g, 3.14 mmol), and acetic acid (0.36 mL, 6.3 mmol) in chloroform (9 mL), and the mixture was stirred at 60°C for 20 hours. After this, the reaction mixture was cooled to room temperature and diluted with chloroform (100 mL). The organic phase was washed with water (40 mL), 1 M aqueous sodium hydroxide (40 mL), and brine (40 mL), then dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, heptane to ethyl acetate, gradient elution) to obtain the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 8.29 (dd, J = 3.0, 0.5 Hz, 1H), 7.46 (dd, J = 8.5, 0.5 Hz, 1H), 7.42 (dd, J = 8.5, 3.0 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 6.96 (d, J = 2.5 Hz, 1H), 6.66 (dd, J = 8.5, 2.5 Hz, 1H), 6.08-6.00 (m, 1H), 5.41 (dq, J = 17.5, 1.5 Hz, 1H), 5.29 (dq, J = 10.5, 1.5 Hz, 1H), 5.07 (s, MS (ESI) m / z 467 [M + H] + . 【0353】 Step 2: tert-butyl 4-(5-((5-hydroxypyridine-2-yl)methoxy)benzo[d]oxazole-2-yl)piperazine-1-carboxylate A mixture of tert-butyl 4-(5-((5-(allyloxy)pyridine-2-yl)methoxy)benzo[d]oxazole-2-yl)piperazine-1-carboxylate (0.347 g, 0.744 mmol) and 1,3-dimethylbarbitulic acid (0.139 g, 0.893 mmol) in anhydrous N,N-dimethylformamide (30 mL) was purged with argon for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.043 g, 0.037 mmol) was added, and the mixture was stirred under argon at room temperature for 6 hours. After this, the reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 × 60 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, dichloromethane, 95:5 dichloromethane / methanol, gradient elution) to obtain the title compound. 1 H NMR (500 MHz, CDCl3) δ 8.20 (d, J = 3.0 Hz, 1H), 7.39-7.34 (m, 2H), 7.17 (dd, J = 8.5, 3.0 Hz, 1H), 7.13 (d, J = 8.5 Hz, 1H), 6.95 (d, J = MS (ESI) m / z 427 [M + H] + . 【0354】 Step 3: tert-butyl4-(5-((5-((3-oxo-2,5,8,11-tetraoxatridecane-13-yl)oxy)-pyridine-2-yl)methoxy)benzo[d]oxazole-2-yl)piperazine-1-carboxylate A solution of tert-butyl 4-(5-((5-hydroxypyridine-2-yl)methoxy)benzo[d]oxazole-2-yl)piperazine-1-carboxylate (0.197 g, 0.462 mmol), methyl 2-(2-(2-(2-hydroxyethoxy)ethoxy)-ethoxy)acetate (0.226 g, 1.02 mmol), and 2-(tributyl-15-phosphanylidene)acetonitrile (0.260 g, 1.08 mmol) in toluene (15 mL) was stirred at 100 °C for 15 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, ethyl acetate to 94:6 ethyl acetate / methanol, gradient elution) to obtain the title compound. 1 H NMR (500 MHz, CDCl3) δ 8.30 (d, J = 2.5 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.24 (dd, J = 8.5, 2.5 Hz, 1H), 7.13 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 2.5 Hz, 1H), 6.69 (dd, J = 8.5, 2.5 Hz, 1H), 5.13 (s, 2H), 4.19-4.17 (m, 2H), 4.16 (s, 2H), 3.88-3.87 (m, 2H), 3.74 (s, 3H), 3.73-3.68 (m, 8H), 3.66-3.64 (m, 4H), 3.56-3.54 (m, 4H), 1.49 (s, 9H); MS (DUIS) m / z 631 [M + H] + . 【0355】 Step 4: 2-(2-(2-(2-((6-(((2-(4-(tert-butoxycarbonyl)piperazine-1-yl)benzo[d]-oxazole-5-yl)oxy)methyl)pyridine-3-yl)oxy)ethoxy)ethoxy)ethoxy)acetic acid A solution of lithium hydroxide (0.031 g, 1.3 mmol) in water (10 mL) was added to a solution of tert-butyl 4-(5-((5-((3-oxo-2,5,8,11-tetraoxatridecane-13-yl)oxy)pyridine-2-yl)methoxy)benzo[d]oxazole-2-yl)piperazine-1-carboxylate (0.175 g, 0.277 mmol) in methanol (40 mL), and the mixture was stirred at room temperature for 5.5 hours. After this, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase chromatography (C18, 95:5 water / acetonitrile to acetonitrile, gradient elution) to obtain the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 12.58 (br s, 1H), 8.29 (dd, J = 2.5, 1.0 Hz, 1H), 7.46 (dd, J = 8.5, 1.0 Hz, 1H), 7.42 (dd, J = 8.5, 2.5 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 6.96 (d, J = 2.5 Hz, 1H), 6.66 (dd, J = 8.5, 2.5 Hz, 1H), 5.07 (s, 2H), 4.19-4.17 (m, 2H), 4.00-3.99 (m, 2H), 3.77-3.75 (m, 2H), 3.60-3.52 (m, 12H), 3.47-3.45 (m, 4H), 1.43 (s, 9H); MS (DUIS) m / z 617 [M + H] + . 【0356】 Step 5: tert-butyl4-(5-((5-(((S)-13-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecyl)oxy)pyridine-2-yl)methoxy)benzo[d]oxazole-2-yl)piperazine-1-carboxylate HATU (0.090 g, 0.24 mmol) is mixed with 2-(2-(2-(2-((6-(((2-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzo[d]oxazole-5-yl)oxy)methyl)pyridine-3-yl)oxy)ethoxy)-ethoxy)ethoxy)acetic acid (0.145 g, 0.235 ml) in N,N-dimethylformamide (6.5 mL). The compound was added to a suspension of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazole-5-yl)benzyl)pyrrolidine-2-carboxamide (0.101 g, 0.235 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.86 mmol), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then diluted with saturated aqueous sodium carbonate (60 mL) and brine (20 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, dichloromethane to 90:10 dichloromethane / methanol, gradient elution) to obtain the title compound. 1¹H NMR (500 MHz, DMSO-d6, mixture of rotational isomers, chemical shifts of the main rotational isomer are listed) δ 8.97 (s, 1H), 8.60 (t, J = 6.0 Hz, 1H), 8.26 (d, J = 2.5 Hz, 1H), 7.45-7.37 (m, 7H), 7.28 (d, J = 8.5 Hz, 1H), 6.96 (d, J = 2.5 Hz, 1H), 6.66 (dd, J = 8.5, 2.5 Hz, 1H), 5.15 (d, J = 3.5 Hz, 1H), 5.06 (s, 2H), 4.56 (d, J = 9.5 Hz, 1H), 4.46-4.42 (m, 1H), 4.41-4.35 (m, 2H), 4.25 (dd, J = 16.0, 5.5 Hz, 1H), 4.16-4.14 (m, 2H), 3.96 (s, 2H), 3.73-3.72 (m, 2H), 3.67 (dd, J = 10.5, 3.5 Hz, 1H), 3.62-3.55 (m, 13H), 3.46-3.44 (m, 4H), 2.43 (s, 3H), 2.08-2.03 (m, 1H), 1.93-1.87 (m, 1H), 1.42 (s, 9H), 0.94 (s, 9H); MS (DUIS) m / z 1029 [M + H] + . 【0357】 Step 6: (2S,4R)-1-((S)-2-(tert-butyl)-4-oxo-14-((6-(((2-(piperazin-1-yl)benzo-[d]oxazole-5-yl)oxy)methyl)pyridine-3-yl)oxy)-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methylthiazole-5-yl)benzyl)pyrrolidine-2-carboxamide Trifluoroacetic acid (4.0 mL, 52 mmol) was added at 0°C to a solution of tert-butyl 4-(5-((5-(((S)-13-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecyl)oxy)pyridine-2-yl)methoxy)benzo[d]oxazole-2-yl)piperazine-1-carboxylate (0.113 g, 0.110 mmol) in dichloromethane (4.0 mL), and the mixture was stirred at 0°C for 1 hour and at room temperature for 1 hour. Subsequently, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase chromatography (C18, 95:5 water / acetonitrile to acetonitrile, 0.1% trifluoroacetic acid additive, gradient elution). The product fraction was added to saturated aqueous sodium bicarbonate (75 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was further purified by reverse-phase chromatography (C18, 95:5 water / acetonitrile to acetonitrile, no additives, packed in 1:1 tetrahydrofuran / water, gradient elution). The product fraction was freeze-dried to obtain the title compound. 1¹H NMR (500 MHz, DMSO-d6, mixture of rotational isomers, chemical shift of the main rotational isomer is indicated) δ 8.97 (s, 1H), 8.60 (t, J = 6.0 Hz, 1H), 8.26 (d, J = 2.5 Hz, 1H), 7.45-7.37 (m, 7H), 7.25 (d, J = 8.5 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 6.63 (dd, J = 8.5, 2.5 Hz, 1H), 5.15 (d, J = 3.5 Hz, 1H), 5.06 (s, 2H), 4.56 (d, J = 9.5 Hz, 1H), 4.46-4.43 (m, 1H), 4.41-4.35 (m, 2H), 4.25 (dd, J = 16.0, 6.0 Hz, 1H), 4.16-4.14 (m, 2H), 3.96 (s, 2H), 3.74-3.72 (m, 2H), 3.67 (dd, J = 11.0, 4.0 Hz, 1H), 3.62-3.56 (m, 9H), 3.49-3.47 (m, 4H), 2.78-2.76 (m, 4H), 2.43 (s, 3H), 2.08-2.04 (m, 1H), 1.93-1.87 (m, 1H), 0.94 (s, 9H);MS (ESI) m / z 929 [M + H] + ; HPLC: Method 1, t R = 4.66 minutes. 【0358】 The following compounds were prepared as described above. 【0359】 [Table 15] 【0360】 [Example 16] Scheme for Example 16 【0361】 [ka] 【0362】 Step 1: tert-butyl 4-(5-((5-methoxypyridine-2-yl)methoxy)benzo[d]oxazole-2-yl)piperazine-1-carboxylate To a solution of 2-amino-4-((5-methoxypyridine-2-yl)methoxy)phenol (0.466 g, 1.89 mmol) in chloroform (15 mL), tert-butylpiperazine-1-carboxylate (0.705 g, 3.78 mmol), acetic acid (0.433 mL, 7.57 mmol), and tetramethoxymethane (0.504 mL, 3.78 mmol) were added, and the mixture was heated overnight at 60°C. The reaction mixture was then cooled to room temperature, diluted with dichloromethane (30 mL), and washed with water (30 mL), 1 M aqueous sodium hydroxide (20 mL), and brine (30 mL). The organic phase was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, dichloromethane to ethyl acetate, gradient elution) to obtain the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 8.28 (dd, J = 2.5, 0.5 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.41 (dd, J = 8.5, 2.5 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 6.96 (d, J = 2.5 Hz, 1H), 6.66 (dd, J = 8.5, 2.5 Hz, 1H), 5.08 (s, 2H), 3.83 (s, 3H), 3.57-3.55 (m, 4H), 3.47-3.44 (m, 4H), 1.43 (s, 9H). 【0363】 Step 2: 5-((5-methoxypyridine-2-yl)methoxy)-2-(piperazine-1-yl)benzo[d]-oxazole To a solution of tert-butyl 4-(5-((5-methoxypyridine-2-yl)methoxy)benzo[d]oxazole-2-yl)piperazine-1-carboxylate (0.060 g, 0.14 mmol) in 1,4-dioxane (4 mL), 4 M hydrogen chloride in 1,4-dioxane (0.25 mL, 1.0 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was partitioned between dichloromethane (10 mL) and 10% aqueous sodium bicarbonate (10 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 × 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 8.28 (dd, J = 3.0, 0.5 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.41 (dd, J = 8.5, 2.5 Hz, 1H), 7.26 (d, J = 8.5 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 6.63 (dd, J = 8.5, 3.0 Hz, 1H), 5.07 (s, 2H), 3.83 (s, 3H), 3.50-3.48 (m, 4H), 2.78-2.76 (m, 4H). 【0364】 Step 3: tert-butyl 2-(2-(2-(2-(4-(5-((5-methoxypyridine-2-yl)methoxy)benzo-[d]oxazole-2-yl)piperazine-1-yl)ethoxy)ethoxy)ethoxy)acetate N,N-diisopropylethylamine (0.21 mL, 1.2 mmol) was added to a solution of 5-((5-methoxypyridine-2-yl)methoxy)-2-(piperazin-1-yl)benzo[d]oxazole (0.150 g, 0.410 mmol) and tert-butyl 2-(2-(2-(2-((methylsulfonyl)oxy)ethoxy)ethoxy)ethoxy)acetate (0.178 g, 0.520 mmol) in acetonitrile (3.5 mL), and the mixture was stirred under reflux for 18 hours. After this, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, dichloromethane to 80:20 dichloromethane / methanol, gradient elution) to obtain the title compound. 1 H NMR (500 MHz, CDCl3) δ 8.29 (d, J = 2.5 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.20 (dd, J = 8.5, 2.5 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 6.97 (d, J = 2.5 Hz, 1H), 6.67 (dd, J = 8.5, 2.5 Hz, 1H), 5.14 (s, 2H), 4.02 (s, 2H), 3.86 (s, 3H), 3.73-3.63 (m, 14H), 2.65 (t, J = 5.5 Hz, 2H), 2.63-2.61 (m, 4H), 1.47 (s, 9H); MS (DUIS) m / z 587 [M + H] + . 【0365】 Step 4: (2S,4R)-1-((S)-2-(tert-butyl)-14-(4-(5-((5-methoxypyridine-2-yl)methoxy)benzo[d]oxazole-2-yl)piperazine-1-yl)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methylthiazole-5-yl)benzyl)pyrrolidine-2-carboxamide Trifluoroacetic acid (1.0 mL, 13 mmol) was added to a solution of tert-butyl 2-(2-(2-(2-(4-(5-((5-methoxypyridine-2-yl)methoxy)benzo[d]oxazole-2-yl)piperazine-1-yl)ethoxy)ethoxy)-ethoxy) acetate (0.156 g, 0.266 mmol) in dichloromethane (1.5 mL), and the mixture was stirred at room temperature for 80 minutes. After this, the reaction mixture was concentrated to dryness, and the solvent was replaced with dichloromethane (2 × 25 mL) to obtain crude 2-(2-(2-(2-(4-(5-((5-methoxypyridine-2-yl)methoxy)benzo[d]oxazole-2-yl)piperazine-1-yl)ethoxy)ethoxy) acetic acid and trifluoroacetate. MS (DUIS) m / z 531 [M + H] + . 【0366】 Crude 2-(2-(2-(2-(4-(5-((5-methoxypyridine-2-yl)methoxy)benzo[d]oxazole-2-yl)piperazine-1-yl)ethoxy)ethoxy)ethoxy)acetic acid, trifluoroacetate (0.266 mmol) was dissolved in N,N-dimethylformamide (3.5 mL), and treated with (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazole-5-yl)benzyl)pyrrolidine-2-carboxamide (0.115 g, 0.266 mmol), N,N-diisopropylethylamine (0.24 mL, 1.4 mmol), and HATU (0.111 g, 0.293 mmol). The mixture was stirred at room temperature for 30 minutes. Subsequently, the reaction mixture was diluted 1:1 with water / saturated aqueous sodium bicarbonate (80 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layer was washed with brine (2 × 30 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, dichloromethane to 80:20 dichloromethane / methanol, gradient elution). The product fraction was concentrated under reduced pressure and freeze-dried with 2:1 acetonitrile / water (7 mL) to obtain the title compound. 1¹H NMR (500 MHz, MeOD; mixture of rotational isomers, chemical shift of the principal rotational isomer is indicated) δ 8.86 (s, 1H), 8.21 (d, J = 2.5 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.45-7.39 (m, 5H), 7.19 (d, J = 8.5 Hz, 1H), 6.90 (d, J = 2.5 Hz, 1H), 6.70 (dd, J = 8.5, 2.5 Hz, 1H), 5.09 (s, 2H), 4.69 (s, 1H), 4.58-4.49 (m, 3H), 4.34 (d, J = 15.5 Hz, 1H), 4.08-4.01 (m, 2H), 3.88-3.85 (m, 4H), 3.79 (dd, J = 11.0, 4.0 Hz, 1H), 3.72-3.62 (m, 14H), 2.68-2.62 (m, 6H), 2.46 (s, 3H), 2.24-2.19 (m, 1H), 2.11-2.05 (m, 1H), 1.04 (s, 9H); MS (ESI) m / z 943 [M + H] + ; HPLC: Method 1, t R = 5.17 minutes. 【0367】 The following compounds were prepared as described above. 【0368】 [Table 16] 【0369】 [Example 17] Scheme for Example 17 【0370】 [ka] 【0371】 Step 1: tert-butyl N-[2-(2-{2-[(5-nitropyridine-2-yl)oxy]ethoxy}ethoxy)ethyl]carbamate A suspension of 2-chloro-5-nitropyridine (100 mg, 0.63 mmol), tert-butyl N-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}carbamate (173 mg, 0.69 mmol), and potassium tert-butoxide (85 mg, 0.76 mmol) in DMF (1 mL) was stirred at ambient temperature for 3 hours. The mixture was partitioned between water and ethyl acetate and extracted three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated to dryness. The crude product was adsorbed onto silica and purified by FCC (silica, heptane, 20-100% ethyl acetate) to obtain the title compound. 1 H NMR (500 MHz, chloroform-d) δ 9.06 (d, J = 2.8 Hz, 1H), 8.35 (dd, J = 9.1, 2.8 Hz, 1H), 6.88 (d, J = 9.1 Hz, 1H), 4.97 (s, 1H), 4.65 - 4.56 (m, 2H), 3.93 - 3.85 (m, 2H), 3.74 - 3.67 (m, 2H), 3.67 - 3.60 (m, 2H), 3.55 (t, J = 5.2 Hz, 2H), 3.36 - 3.26 (m, 2H), 1.44 (s, 9H). Tr(METCR1410) = 1.12 minutes, (ES + ) [M+Na] + 394. 【0372】 Step 2: tert-butyl N-[2-(2-{2-[(5-aminopyridine-2-yl)oxy]ethoxy}ethoxy)ethyl]carbamate Iron powder (120 mg, 2.15 mmol) was added to a solution of NH4Cl (144 mg, 2.69 mmol) and tert-butyl N-[2-(2-{2-[(5-nitropyridine-2-yl)oxy]ethoxy}ethoxy)ethyl]carbamate (200 mg, 0.54 mmol) in EtOH (10 mL) and water (1 mL). The mixture was heated under reflux for 90 minutes, then cooled to room temperature and filtered through Celite. The filtrate was evaporated to dryness and partitioned between water and ethyl acetate. The aqueous layer was extracted once more with ethyl acetate. The combined layers were washed with brine, dried over MgSO4, filtered, and evaporated to dryness to obtain the title compound. 1 H NMR (250 MHz, chloroform-d) δ 7.62 (dd, J = 3.0, 0.7 Hz, 1H), 7.02 (dd, J = 8.7, 3.0 Hz, 1H), 6.64 (dd, J = 8.7, 0.7 Hz, 1H), 5.04 (s, 1H), 4.43 - 4.36 (m, 2H), 3.86 - 3.79 (m, 2H), 3.74 - 3.60 (m, 4H), 3.54 (t, J = 5.1 Hz, 2H), 3.47 - 3.24 (m, 4H), 1.43 (s, 9H). 0.87 minutes, (ES + ) [M+H] + 342. 【0373】 Step 3: tert-butyl N-[2-(2-{2-[(5-{1,8,10-triazatricyclo[7.4.0.0 2,7 Trideca-2,4,6,8,10,12-hexaene-11-amide}pyridine-2-yl)oxy]ethoxy}ethoxy)ethyl]carbamate 1,8,10-Triazatricyclo[7.4.0.0 2,7Trideca-2(7), 3,5,8,10,12-hexaene-11-carboxylic acid (108 mg, 0.51 mmol) and HATU (212 mg, 0.56 mmol) were dissolved in DMF (4 mL). DIPEA (206 μL, 1.18 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. A solution of tert-butyl N-[2-(2-{2-[(5-aminopyridine-2-yl)oxy]ethoxy}ethoxy)ethyl]carbamate (173 mg, 0.51 mmol) in DMF (1 mL) was added, and the solution was stirred at room temperature under N2 for 3 hours, then diluted with water (5 mL). The deep yellow solid precipitated from the mixture was ground for 5 minutes, filtered, and washed with water. The solid was dried overnight in a vacuum oven at 40°C to obtain the title compound. 1 H NMR (250 MHz, chloroform-d) δ 9.89 (s, 1H), 8.99 (d, J = 7.0 Hz, 1H), 8.51 (d, J = 2.7 Hz, 1H), 8.15 (dd, J = 8.9, 2.7 Hz, 1H), 8.08 (dd, J = 8.3, 1.0 Hz, 1H), 7.99 (dd, J = 8.2, 1.0 Hz, 1H), 7.91 (d, J = 7.0 Hz, 1H), 7.68 (ddd, J = 8.3, 7.2, 1.0 Hz, 1H), 7.53 (ddd, J = 8.2, 7.2, 1.0 Hz, 1H), 6.87 (d, J = 8.9 Hz, 1H), 5.04 (s, 1H), 4.65 - 4.40 (m, 2H), 3.95 - 3.84 (m, 2H), 3.77 - 3.62 (m, 4H), 3.56 (d, J = 5.2 Hz, 2H), 3.32 (d, J = 5.2 Hz, 2H), 1.44 (s, 9H). Tr(METCR1410) = 1.09 minutes, (ES + ) [M+H] + 537. 【0374】 Step 4: N-(6-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}pyridine-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7Trideca-2,4,6,8,10,12-hexaene-11-carboxamide TFA (1 mL) is added to tert-butyl N-[2-(2-{2-[(5-{1,8,10-triazatricyclo[7.4.0.0 2,7 The compound was added dropwise to a solution of trideca-2,4,6,8,10,12-hexaen-11-amide}pyridine-2-yl)oxyethoxy)ethoxy)ethyl]carbamate (200 mg, 0.373 mmol). The mixture was heated to room temperature for 2 hours, then partitioned between saturated NaHCO3 (aq) and DCM. The aqueous layer was separated and extracted three times with DCM and once with 5% MeOH in DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated to dryness to obtain the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.77 (d, J = 7.0 Hz, 1H), 8.69 (d, J = 2.7 Hz, 1H), 8.43 (d, J = 8.2 Hz, 1H), 8.22 (dd, J = 8.9, 2.7 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.76 (d, J = 7.0 Hz, 1H), 7.64 (dd,J = 8.2, 7.9 Hz, 1H), 7.52 (dd, J = 8.2, 7.9 Hz, 1H), 6.90 (d, J = 8.9 Hz, 1H), 4.47 - 4.32 (m, 2H), 3.82 - 3.67 (m, 2H), 3.65 - 3.52 (m, 4H), 3.43 (t, J = 5.5 Hz, 2H), 2.74 (t, J = 5.5 Hz, 2H). Tr(METCR1410) = 0.82 min, (ES + ) [M+H] + 437. 【0375】 Step 5: tert-butyl N-[(1S,2R)-1-hydroxy-1-{[(1S)-3-methyl-1-{[2-(2-{2-[(5-{1,8,10-triazatricyclo[7.4.0.0 2,7Trideca-2,4,6,8,10,12-hexaen-11-amide}pyridine-2-yl)oxy]ethoxy}ethoxy)ethyl]carbamoyl}butyl]carbamoyl}-3-phenylpropane-2-yl]carbamate N-(6-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}pyridine-3-yl)-1,8,10-triazatricyclo[7.4.0.0] in DMF (1 mL) 2,7 EDC.HCl (62 mg, 0.323 mmol) was added at 0°C to a mixture of trideca-2,4,6,8,10,12-hexaene-11-carboxamide (36 mg, 0.081 mmol), (2S)-2-[[(2S,3R)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenyl-butanoyl]amino]-4-methylpentanoic acid (36 mg, 0.081 mmol), HOBT (28 mg, 0.182 mmol), and DIPEA (63 μL, 0.364 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was partitioned between water (10 mL) and ethyl acetate (10 mL). The phases were separated, and the aqueous layer was extracted with a further ethyl acetate (3 × 10 mL). The combined organic layers were washed with 10% citric acid (aq) (10 mL), saturated NaHCO3 (aq) (2 × 10 mL), and brine (1 × 10 mL), dried over MgSO4, filtered, and evaporated to dryness. The crude product was purified by FCC (silica, 0-6% MeOH in DCM) to obtain the title compound. 1H NMR (500 MHz, methanol-d4) δ 9.50 (d, J = 7.0 Hz, 1H), 8.62 (d, J = 2.7 Hz, 1H), 8.24 (dd, J = 8.2, 1.0 Hz, 1H), 8.15 (dd, J = 8.9, 2.7 Hz, 1H), 7.92 (dd, J = 8.3, 1.0 Hz, 1H), 7.83 (d, J = 7.0 Hz, 1H), 7.66 (ddd, J = 8.3, 7.1, 1.0 Hz, 1H), 7.53 (td, J = 8.2, 7.1, 1.0 Hz, 1H), 7.29 - 7.11 (m, 5H), 6.86 (d, J = 8.9 Hz, 1H), 4.52 - 4.40 (m, 3H), 4.15 (td, J = 7.7, 2.3 Hz, 1H), 4.07 - 3.96 (m, 1H), 3.90 - 3.80 (m, 2H), 3.68 (dd, J = 5.9, 3.3 Hz, 2H), 3.65 - 3.59 (m, 2H), 3.53 (t , J = 5.5 Hz, 2H), 3.42 - 3.34 (m, 2H), 2.94 - 2.79 (m, 2H), 1.77 - 1.50 (m, 2H), 1.33 (s, 9H), 0.99 - 0.81 (m, 6H). Tr(MET-uPLC-AB-101) = 3.46 minutes, (ES + ) [M+H] + 827. 【0376】 Step 6: N-{6-[2-(2-{2-[(2S)-2-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutanamide]-4-methylpentanamide]ethoxy}ethoxy)ethoxy]pyridine-3-yl}-1,8,10-triazatricyclo[7.4.0.0 2,7 Trideca-2,4,6,8,10,12-hexaene-11-carboxamide tert-butyl N-[(1S,2R)-1-hydroxy-1-{[(1S)-3-methyl-1-{[2-(2-{2-[(5-{1,8,10-triazatricyclo[7.4.0.0 2,7 A mixture of trideca-2,4,6,8,10,12-hexaen-11-amide}pyridine-2-yl)oxy]ethoxy}ethoxy)ethyl]carbamoyl}butyl]carbamoyl}-3-phenylpropan-2-yl]carbamate (47.6 mg, 0.57 mmol) was stirred at room temperature. The mixture was sonicated at room temperature for 10 minutes, then stirred at room temperature for 4 hours. The reaction mixture was diluted with MeOH and then evaporated to dryness. The crude product was partitioned between saturated NaHCO3 (25 mL) and DCM (25 mL). The phases were separated, and the aqueous layer was extracted with further DCM (4 × 15 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated to dryness. The crude product was adsorbed onto silica and purified by FCC (silica, 0-20% MeOH in DCM). The combined fraction was evaporated to dryness to obtain the title compound. 1H NMR (500 MHz, methanol-d4) δ 9.50 (d, J = 7.0 Hz, 1H), 8.62 (d, J = 2.7 Hz, 1H), 8.25 (dd, J = 8.4, 1.0 Hz, 1H), 8.15 (dd, J = 8.8, 2.7 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 7.0 Hz, 1H), 7.67 (ddd, J = 8.3, 7.1, 1.1 Hz, 1H), 7.54 (ddd, J = 8.2, 7.1, 1.0 Hz, 1H), 7.34 - 7.10 (m, 5H), 6.86 (d, J = 8.8 Hz, 1H), 4.50 - 4.37 (m, 3H), 3.95 (d, J = 3.1 Hz, 1H), 3.87 - 3.78 (m, 2H), 3.71 - 3.64 (m, 2H), 3.63 - 3.58 (m, 2H), 3.52 (t, J = 5.5 Hz, 2H), 3.39 - 3.32 (m, 3H), 2.90 (dd, J = 13.4, 6.9 Hz, 1H), 2.66 (dd, J = 13.4, 7.8 Hz, 1H), 1.69 - 1.59 (m, 3H), 0.95 (d, J = 6.1 Hz, 3H), 0.93 (d, J = 6.2 Hz, 3H). Tr(METCR1603) = 4.00 minutes, (ES) + [M+H] + 727. 【0377】 The following compounds were prepared as described above. 【0378】 [Table 17] 【0379】 [Example 18] Scheme for Example 18 【0380】 [ka] 【0381】 Step 1: tert-butyl N-[2-(2-{2-[(5-nitropyridine-2-yl)amino]ethoxy}ethoxy)ethyl]carbamate Triethylamine (198 μl, 1.42 mmol) was added dropwise to a solution of 2-chloro-5-nitropyridine (150 mg, 0.95 mmol) and tert-butyl N-{2-[2-(2-aminoethoxy)ethoxy]ethyl}carbamate (282 mg, 1.14 mmol) in MeCN (1.5 mL). The mixture was stirred under reflux in a sealed tube for 4 hours, then cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated to dryness. The crude product was adsorbed onto silica and purified by FCC (silica, heptane, 25-100% ethyl acetate) to obtain the title compound. 1 H NMR (500 MHz, chloroform-d) δ 9.02 (d, J = 2.6 Hz, 1H), 8.16 (s, 1H), 6.57 - 6.36 (m, 1H), 6.08 (s, 1H), 5.52 (s, 1H), 3.74 - 3.49 (m, 10H), 3.35 (d, J = 6.6 Hz, 2H), 1.45 (s, 9H). Tr(METCR1410) = 1.09 min, (ES + ) [M+H] + 371. 【0382】 Step 2: tert-butyl N-[2-(2-{2-[(5-aminopyridine-2-yl)amino]ethoxy}ethoxy)ethyl]carbamate Iron powder (175 mg, 0.79 mmol) was added to a solution of NH4Cl (210 mg, 3.93 mmol) and tert-butyl N-[2-(2-{2-[(5-nitropyridine-2-yl)amino]ethoxy}ethoxy)ethyl]carbamate (291 mg, 0.54 mmol) in EtOH (10 mL) and water (1 mL). The mixture was heated under reflux for 2 hours. Further NH4Cl (100 mg) and iron powder (50 mg) were added, and the reaction was stirred under reflux for 1 hour. The reaction was cooled to room temperature and filtered through Celite while washing with EtOH. The filtrate was evaporated to dryness and then purified by FCC (silica, 0-20% MeOH in DCM) to obtain the title compound. 1 H NMR (500 MHz, chloroform-d) δ 9.02 (d, J = 2.6 Hz, 1H), 8.16 (s, 1H), 6.57 - 6.36 (m, 1H), 6.08 (s, 1H), 5.52 (s, 1H), 3.74 - 3.49 (m, 10H), 3.35 (d, J = 6.6 Hz, 2H), 1.45 (s, 9H). Tr(METCR1410) = 0.80 min, (ES) + [M+H] + 341. 【0383】 Step 3: tert-butyl N-[2-(2-{2-[(5-{1,8,10-triazatricyclo[7.4.0.0 2,7 Trideca-2,4,6,8,10,12-hexaen-11-amide}pyridine-2-yl)amino]ethoxy}ethoxy)ethyl]carbamate 1,8,10-Triazatricyclo[7.4.0.0 2,7Trideca-2(7), 3,5,8,10,12-hexaene-11-carboxylic acid (137 mg, 0.64 mmol) and HATU (270 mg, 0.71 mmol) were dissolved in DMF (4 mL). DIPEA (262 μL, 1.51 mmol) was added and the reaction mixture was stirred for 5 minutes. A solution of tert-butyl N-[2-(2-{2-[(5-aminopyridine-2-yl)amino]ethoxy}ethoxy)ethyl]carbamate (220 mg, 0.64 mmol) in DMF (1 mL) was added and the solution was stirred for 18 hours at room temperature under N2. Water (10 mL) was added to the mixture to induce precipitation of the product. The resulting suspension was stirred at room temperature for 10 minutes, filtered, and washed with further water. The solid was dried to the title compound in a vacuum oven at 40°C overnight. 1 H NMR (500 MHz, chloroform-d) δ 9.84 (s, 1H), 8.99 (d, J = 7.0 Hz, 1H), 8.55 (s, 1H), 8.07 (d, J = 8.3 Hz, 1H), 8.00 - 7.98 (m, 2H), 7.90 (d, J = 7.0 Hz, 1H), 7.68 (ddd, J = 8.3, 7.1, 1.1 Hz, 1H), 7.54 (td, J = 8.2, 7.1, 1.1 Hz, 1H), 6.67 (s, 1H), 5.78 (s, 1H), 5.28 (s, 1H), 3.75 (t, J = 5.0 Hz, 2H), 3.69 - 3.63 (m, 4H), 3.61 - 3.56 (m, 4H), 3.35 (s, 2H), 1.44 (s, 9H). Tr(METCR1410) = 0.94 min, (ES + ) [M+H] + 536. 【0384】 Step 4: 2-(2-{2-[(5-{1,8,10-Triazatricyclo[7.4.0.0 2,7 Trideca-2,4,6,8,10,12-hexaene-11-amide}pyridine-2-yl)amino]ethoxy}ethoxy)ethane-1-aminium chloride tert-butyl N-[2-(2-{2-[(5-{1,8,10-triazatricyclo[7.4.0.0 2,7 [Trideca-2,4,6,8,10,12-hexaen-11-amide]pyridine-2-yl)amino]ethoxy]ethoxy)ethyl]carbamate (250 mg, 0.45 mmol) was dissolved in HCl (4N in dioxane, 5 mL, 20 mmol), and the resulting mixture was stirred at room temperature for 4 hours. The reaction product was evaporated to dryness to obtain the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 11.38 (s, 1H), 9.90 (d, J = 7.0 Hz, 1H), 9.02 (s, 1H), 8.63 (d, J = 2.5 Hz, 1H), 8.51 (d, J = 8.3 Hz, 1H), 8.37 (dd, J = 9.7, 2.5 Hz, 1H), 8.06 - 7.95 (m, 4H), 7.89 (d, J = 6.9 Hz, 1H), 7.70 (t, J = 7.7 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.27 (d, J = 9.7Hz, 1H), 3.69 - 3.53 (m, 10H), 2.96 (q, J = 5.6 Hz, 2H). Tr(METCR1410) = 0.78 min, (ES + ) [M+H] + 436. 【0385】 Step 5: tert-butyl N-[(1S,2R)-1-hydroxy-1-{[(1S)-3-methyl-1-{[2-(2-{2-[(5-{1,8,10-triazatricyclo[7.4.0.0 2,7 ]Trideca-2,4,6,8,10,12-hexaen-11-amide}pyridine-2-yl)amino]ethoxy}ethoxy)ethyl]carbamoyl}butyl]carbamoyl}3-phenylpropane-2-yl]carbamate 2-(2-{2-[(5-{1,8,10-triazatricyclo[7.4.0.0 2,7EDC.HCl (162 mg, 0.85 mmol) was added at 0°C to a mixture of trideca-2,4,6,8,10,12-hexaen-11-amide}pyridine-2-yl)amino]ethoxy}ethoxy)ethane-1-aminium chloride (100 mg, 0.21 mmol), (2S)-2-[[(2S,3R)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenyl-butanoyl]amino]-4-methylpentanoic acid (94 mg, 0.21 mmol), HOBT (73 mg, 0.48 mmol), and DIPEA (240 μL, 1.38 mmol). The reaction mixture was stirred at room temperature for 7 hours. The reaction product was partitioned between water (50 mL) and ethyl acetate (50 mL). The phases were separated, and the aqueous layer was further extracted with toluene (2 × 15 mL). The combined organic layers were washed with 10% citric acid (1 × 30 mL), saturated NaHCO3 (2 × 30 mL), and brine (30 mL). The organic layers were dried over Na2SO4, filtered, and evaporated to dryness. The crude product was purified by FCC (silica, 0-10% MeOH in DCM) to obtain the title compound. 1H NMR (500 MHz, methanol-d4) δ 9.42 (d, J = 7.0 Hz, 1H), 8.45 (d, J = 2.6 Hz, 1H), 8.19 (d, J = 8.3 Hz, 1H), 7.90 - 7.84 (m, 2H), 7.77 (d, J = 7.0 Hz, 1H), 7.62 (ddd, J = 8.3, 7.1, 1.1 Hz, 1H), 7.49 (ddd, J = 8.2, 7.1, 1.0 Hz, 1H), 7.28 - 7.12 (m, 5H), 6.58 (d, J = 8.9 Hz, 1H), 6.25 (d, J = 9.6 Hz, 1H), 4.48 (dd, J = 9.3, 5.5 Hz, 1H), 4.23 - 4.09 (m, 1H), 4.09 - 3.93 (m, 1H), 3.70 - 3.57 (m, 6H), 3.53 (t, J = 5.4 Hz, 2H), 3.45 (t, J = 5.4 Hz, 2H), 3.41 - 3.32 (m, 2H), 2.87 (dd, J = 13.4, 7.7 Hz, 1H), 2.82 (dd, J = 13.4, 7.7 Hz, 1H), 1.71 - 1.52 (m, 3H), 1.33 (s, 9H), 0.93 (d, J = 6.4 Hz, 3H), 0.90 (d, J = 6.4 Hz, 3H). Tr(MET-uPLC-AB-101) = 2.51 min, (ES + ) [M+H] + 826. 【0386】 Step 6: N-(6-{[2-(2-{2-[(2S)-2-[(2S,3R)-3-azaniumyl-2-hydroxy-4-phenylbutanamide]-4-methylpentanamide]ethoxy}ethoxy)ethyl]amino}pyridine-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 Trideca-2,4,6,8,10,12-hexaene-11-carboxamide formate tert-butyl N-[(1S,2R)-1-hydroxy-1-{[(1S)-3-methyl-1-{[2-(2-{2-[(5-{1,8,10-triazatricyclo[7.4.0.0 2,7 A mixture of ]trideca-2,4,6,8,10,12-hexaen-11-amide}pyridine-2-yl)amino]ethoxy}ethoxy)ethyl]carbamoyl}butyl]carbamoyl}-3-phenylpropan-2-yl]carbamate (96 mg, 0.116 mmol) was stirred at room temperature for 4 hours. The mixture was concentrated under vacuum and partitioned between DCM (25 mL) and saturated NaHCO3 (50 mL). The aqueous layer was extracted with DCM (4 × 25 mL), the combined extracts were washed with brine, dried over MgSO4, filtered, and evaporated to dryness. The crude product was purified by FCC (silica, 0-15% MeOH in DCM) and by acid reverse-phase chromatography (C-18, 0-100% MeCN / water + 0.1% formic acid) to obtain the title compound. 1H NMR (500 MHz, methanol-d4) δ 9.50 (d, J = 7.0 Hz, 1H), 8.47 (d, J = 2.6 Hz, 1H), 8.38 (s, 1H), 8.25 (d, J = 8.2 Hz, 1H), 7.94 - 7.88 (m, 2H), 7.82 (d, J = 7.0 Hz, 1H), 7.67 (ddd, J = 8.3, 7.1, 1.1 Hz, 1H), 7.54 (ddd, J = 8.2, 7.0, 1.0 Hz, 1H), 7.32 - 7.22 (m, 5H), 6.64 (d, J = 9.0 Hz, 1H), 4.39 (dd, J = 8.6, 6.3 Hz, 1H), 4.17 (d, J = 3.1 Hz, 1H), 3.81 (td, J = 7.5, 3.1 Hz, 1H), 3.68 (t, J = 5.5 Hz, 2H), 3.64 - 3.58 (m, 4H), 3.53 (t, J = 5.5 Hz, 2H), 3.48 (t, J = 5.4 Hz, 2H), 3.42 - 3.33 (m, 2H), 3.11 (dd, J = 13.9, 7.9 Hz, 1H), 2.92 (dd, J = 13.9 , 7.0 Hz, 1H), 1.82 - 1.54 (m, 3H), 0.93 (s, 6H). Tr(MET-uHPLC-AB-101) = 1.53 min, (ES) + [M+H] + 726. 【0387】 The following compounds were prepared as described above. 【0388】 [Table 18] 【0389】 [Example 19] Scheme for Example 19 【0390】 [ka] 【0391】 Step 1: tert-butyl N-[2-[2-[2-[7-cyano-3-(methylamino)imidazo[1,2-a]pyridine-2-yl]imidazo[2,1-b][1,3]benzothiazole-6-yl]oxyethoxy]ethyl]carbamate CMBP (0.33 mL, 1.23 mmol) was added to a suspension of 2-(6-hydroxyimidazo[2,1-b][1,3]benzothiazole-2-yl)-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile (192 mg, 0.533 mmol) and tert-butyl N-[2-(2-hydroxyethoxy)ethyl]carbamate (219 mg, 1.07 mmol) in toluene (5 mL). The reaction mixture was stirred at 100°C for 2 hours. The reaction mixture was then cooled to room temperature, the resulting precipitate was filtered, washed with toluene, and the title compound was obtained. 1 H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.34 (dd,J = 7.1, 0.7 Hz, 1H), 8.14 (d,J = 0.9 Hz, 1H), 8.03 (d, J = 8.9 Hz, 1H), 7.69 (d, J = 2.5 Hz, 1H), 7.17 (dd, J = 8.9, 2.4 Hz, 1H), 7.11 (dd, J = 7.1, 1.6 Hz, 1H), 6.79 (s, 1H), 5.63 (q, J = 5.8 Hz, 1H), 4.29 - 4.09 (m, 2H), 3.80 - 3.68 (m, 2H), 3.47 (t, J = 6.1 Hz, 2H), 3.11 (q, J = 5.9 Hz, 2H), 2.89 (d, J = 5.9 Hz, 3H), 1.37 (s, 9H). Tr(METCR1410) = 1.20 min, (ES + ) (M+H) + 548. 【0392】 Step 2: 2-[6-[2-(2-aminoethoxy)ethoxy]imidazo[2,1-b][1,3]benzothiazole-2-yl]-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile hydrochloride 4M HCl in dioxane (0.83 mL, 3.33 mmol) was added dropwise to a solution of 1,4-dioxane (5 mL) and tert-butyl N-[2-[2-[2-[7-cyano-3-(methylamino)imidazo[1,2-a]pyridine-2-yl]imidazo[2,1-b][1,3]benzothiazole-6-yl]oxyethoxy]ethyl]carbamate (198 mg, 0.333 mmol) in MeOH (2.5 mL). The mixture was stirred at room temperature for 24 hours, after which 4N HCl in an additional 0.20 mL of dioxane was added, and the mixture was stirred at room temperature for another 24 hours. The reaction product was evaporated to dryness to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.46 (s, 1H), 8.20 (s, 1H), 8.07 (d, J = 8.9 Hz, 1H), 7.88 (s, 3H), 7.72 (s, 1H), 7.40 - 7.12 (m, 2H), 4.26 - 4.18 (m, 2H), 3.90 - 3.80 (m, 2H), 3.69 (t, J = 5.2 Hz, 2H), 3.02 (q, J = 5.5 Hz, 2H), 2.90 (s, 3H). 0.87 minutes, (ES + ) (M+H) + 448. 【0393】 Step 3: 2-[6-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindoline-4-yl]amino]ethoxy]ethoxy]imidazo[2,1-b][1,3]benzothiazole-2-yl]-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile (compound 9) DIPEA (0.072 mL, 0.413 mmol) was added to a suspension of 2-(2,6-dioxo-3-piperidyl)-4-fluoroisoindoline-1,3-dione (57 mg, 0.207 mmol) and 2-[6-[2-(2-aminoethoxy)ethoxy]imidazo[2,1-b][1,3]benzothiazole-2-yl]-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrilate hydrochloride (100 mg, 0.207 mmol) in DMF (2.5 mL). The solution was heated at 90°C for 48 hours. The reaction product was evaporated to dryness and purified by low pH prep HPLC to obtain the title compound. 1 H NMR (500 MHz, DMSO-d6) d 11.10 (s, 1H), 8.68 (s, 1H), 8.35 (d, J = 7.1 Hz, 1H), 8.14 (s, 1H), 7.99 (d, J = 8.9 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.60 - 7.54 (m, 1H), 7.18 - 7.13 (m, 2H), 7.11 (dd, J = 7.1, 1.6 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.64 (t, J = 5.7 Hz, 1H), 5.63 (q, J = 5.8 Hz, 1H), 5.04 (dd, J = 12.8, 5.4 Hz, 1H), 4.29 - 4.07 (m, 2H), 3.95 - 3.76 (m, 2H), 3.72 (t, J = 5.4 Hz, 2H), 3.51 (q, J = 5.4 Hz, 2H), 2.95 - 2.81 (m, 4H), 2.71 - 2.54 (m, 1H), 2.53 - 2.51 (m, 1H), 2.08 - 1.95 (m, 1H). Tr(MET-uHPLC-AB-101) = 3.36 min m / z (ES + ) (M+H) + 704.3. 【0394】 [Example 20] Scheme for Example 20 【0395】 [ka] 【0396】 Step 1: 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethylmethanesulfonate A stirred solution of tert-butyl N-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}carbamate (250 mg, 1.00 mmol) and NEt3 (181 μL, 1.3 mmol) in 5 mL of DCM at 0°C was treated with dropwise addition of MsCl (93 μL, 1.2 mmol). After addition, the mixture was stirred at 0°C for 1.5 hours, then at room temperature for 3 hours. The reaction mixture was diluted with 10 mL of DCM and washed with a solution of saturated NaHCO3 (15 mL) and brine (15 mL). The organic layer was dried over MgSO4, filtered, concentrated under vacuum, and further dried on a high vacuum line for 2 hours to obtain the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 6.78 - 6.70 (m, 1H), 4.35 - 4.25 (m, 2H), 3.70 - 3.65 (m, 2H), 3.55 (dd, J = 5.9, 3.2 Hz, 2H), 3.51 (dd, J = Tr (METCR1410) = 0.97 min, (ES + ) [MH-Boc] + 228. 【0397】 Step 2: tert-butyl N-[2-[2-(2-iodoethoxy)ethoxy]ethyl]carbamate To a stirred solution of tert-butyl N-(2-{2-[2-(methanesulfonyloxy)ethoxy]ethoxy}ethyl) carbamate (333 mg, 1.02 mmol) in dry acetone (8 mL), KI (675 mg, 4.06 mmol) was added. The resulting suspension was stirred overnight at 50°C. The reaction mixture was then cooled to room temperature, diluted with dry acetone (10 mL), and treated with KI (675 mg, 4.06 mmol). The reaction mixture was stirred overnight at 50°C. The reaction mixture was then treated with KI (300 mg, 1.81 mmol) and heated for 3 hours. The reaction mixture was then cooled to room temperature and partitioned between water (10 mL) and ethyl acetate (10 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (4 × 15 mL). The combined organic phases were washed with a solution of saturated Na2S2O3(aq) (20 mL) and brine (20 mL), dried over MgSO4, filtered, and concentrated under vacuum to obtain the crude product. The crude product was pre-absorbed onto silica and purified by FCC (silica, heptane, 0-100% siRNA). The pure fractions were combined, concentrated under vacuum, and further dried on a high vacuum line for 2 hours to obtain the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 6.72 (t, J = 5.1 Hz, 1H), 3.66 (t, J = 6.4 Hz, 2H), 3.55 (dd, J = 5.8, 3.2 Hz, 2H), 3.51 (dd, J = 5.8, 3.3 Hz, 2H), 3.39 (t, J = 6.1 Hz, 2H), 3.35 - 3.31 (m, 2H), 3.06 (q, J = 6.0 Hz, 2H), 1.37 (s, 9H). Tr (METCR1410) = 1.13 min, (ES + ) [MH-Boc] + 260.0 【0398】 Step 3: Methyl 2-anilinopyrimidine-4-carboxylate In a sealed tube, methyl 2-chloropyrimidine-4-carboxylate (250 mg, 1.45 mmol) was added in dioxane (2 mL), followed by aniline (135 μL, 1.45 mmol) and acetic acid (158 μL, 2.9 mmol). The tube was flushed with nitrogen and placed on a preheated heating block set to 100°C. The mixture was stirred for 1 hour, then stirred overnight at room temperature. The reaction mixture was heated further at 100°C for 5 hours, then left at room temperature over the weekend. The reaction mixture was heated for a further 6 hours, then left to cool to room temperature. The red solution was then diluted with saturated NaHCO3 (8 mL), and the resulting mixture was extracted with toluene (4 × 15 mL). The combined organic matter was washed with brine (15 mL), dried over MgSO4, filtered, and concentrated under vacuum to obtain the crude product. The crude material was pre-absorbed into silica and purified by FCC (0-100% toluene in heptane) to obtain the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.73 (d, J = 4.9 Hz, 1H), 7.81 (d, J = 7.7 Hz, 2H), 7.32 (d, J = 4.9 Hz, 1H), 7.31 - 7.26 (m, 2H), 6.98 (t, J = 7.3 Hz, 1H), 3.91 (s, 3H). Tr (METCR1603) = 3.93 min, (ES + ) [M+H] + 230.1. 【0399】 Step 4: 2-[N-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethyl]anilino]pyrimidine-4-carboxylic acid A sealed tube was packed with methyl 2-(phenylamino)pyrimidine-4-carboxylate (103 mg, 0.45 mmol) in DMF (2 mL) and cooled to 0°C (ice / water). Sodium hydride (60%, 20 mg, 0.49 mmol) was added all at once, and the mixture was stirred for 15 minutes. A solution of tert-butyl N-[2-[2-(2-iodoethoxy)ethoxy]ethyl]carbamate (241 mg, 0.67 mmol) in DMF (2 mL) was then added over 2 minutes, and the mixture was further stirred at 0°C for 10 minutes, at room temperature for 1.5 hours, at 50°C for 4 hours, and at 80°C overnight. The reaction mixture was then cooled to room temperature and concentrated under vacuum to obtain the product. The product was suspended in THF (2 mL) and treated with 1 M LiOH (1 mL). The mixture was briefly sonicated and stirred at room temperature for 2.5 hours. Subsequently, the reaction mixture was concentrated in a vacuum, and the remaining aqueous substance was extracted with ether (3 × 5 mL). The aqueous phase was then acidified to pH 4 by adding a solution of 10% citric acid (aq) (2 mL). The mixture was extracted with toluene (3 × 15 mL). The combined organic extract was washed with brine (15 mL), dried over MgSO4, filtered, concentrated in a vacuum, and further dried in a vacuum oven to obtain the crude product. The crude residue was purified by acidic reverse-phase biotage (C-18, 0-100% MeCN / water + 0.1% formic acid) to obtain the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 8.50 (d, J = 4.8 Hz, 1H), 7.40 (t, J = 7.8 Hz, 2H), 7.33 (dd, J = 8.4, 1.2 Hz, 2H), 7.25 (t, J = 7.3 Hz, 1H), 7.15 (d, J = 4.8 Hz, 1H), 6.70 (t, J = 4.9 Hz, 1H), 4.12 (t, J = 6.1 Hz, 2H), 3.62 (t, J = 6.1 Hz, 2H), 3.47 (dd, J = 5.8, 3.3 Hz, 2H), 3.43 (dd, J = 5.7, 3.2 Hz, 2H), 3.34 (s, 2H), 3.02 (q, J = 5.9 Hz, 2H), 1.35 (s, 9H). Tr(METCR1410) = 1.12 min, (ES +) [M+H] + 447.2. 【0400】 Step 5: tert-butyl N-[2-[2-[2-(N-[4-[(6-methoxy-3-pyridyl)carbamoyl]pyrimidine-2-yl]anilino)ethoxy]ethoxy]ethyl]carbamate A stirred solution of 2-[N-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethyl]anilino]pyrimidine-4-carboxylic acid (57 mg, 0.1 mmol) and N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridine-3-yloxy)methylidene]-N-methylmethaneaminium hexafluorophosphate (58 mg, 0.15 mmol) in DMF (2 mL) was stirred under nitrogen at 0°C, and treated by dropwise addition of N-ethyl-N-(propan-2-yl)propan-2-amine (24 μL, 0.14 mmol). The reaction mixture was stirred at 0°C for 10 minutes, and then treated with a solution of 6-methoxypyridine-3amine (15.79 mg, 0.13 mmol) in DMF (1 mL). The resulting mixture was stirred at 0°C for 2 hours, then at room temperature overnight. The reaction mixture was then concentrated under vacuum, and the residue was partitioned between DCM (10 mL) and water (10 mL). The layers were separated, and the aqueous phase was extracted with DCM (3 × 10 mL). The combined organic matter was washed with brine (15 mL). The layers were separated, and the aqueous phase was extracted with DCM (10 mL). The combined organic phase was dried over MgSO4, filtered, and concentrated under vacuum to obtain the crude residue. The crude residue was pre-absorbed onto silica and purified by FCC (silica, heptane, 0-100% toluene) to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.56 (d, J = 4.8 Hz, 1H), 8.45 (d, J = 2.5 Hz, 1H), 8.00 (dd, J = 8.9, 2.7 Hz, 1H), 7.47 - 7.42 (m, 2H), 7.42 - 7.36 (m, 2H), 7.32 - 7.25 (m, 2H), 6.88 (d, J = 8.8 Hz, 1H), 6.68 (t, J = 5.4 Hz, 1H), 4.29 (t, J = 5.8 Hz, 2H), 3.85 (s, 3H), 3.66 (t, J = 5.8 Hz, Tr(METCR1410) = 1.31 minutes, (ES + ) [M+H] + 553. 【0401】 Step 6: 2-[N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]anilino]-N-(6-methoxy-3-pyridyl)pyrimidine-4-carboxamide hydrochloride tert-butyl N-[2-[2-[2-(N-[4-[(6-methoxy-3-pyridyl)carbamoyl]pyrimidine-2-yl]anilino)ethoxy]ethoxy]ethyl]carbamate (59.5 mg, 0.11 mmol) was treated with 4 M HCl in dioxane (1.12 mL), diluted with MeOH (2 mL), and the resulting solution was stirred at room temperature for 5 hours. The reaction mixture was then concentrated under vacuum and further dried in a vacuum oven at 50°C to obtain the title compound. The title compound was obtained as a 1:1 mixture of the title compound and the O-demethylation product. Tr(METCR1410) = 0.95 min, (ES + ) [M+H] + 453.1. 【0402】 Step 7: 2-[N-[2-[2-[2-[[(2S)-2-[[(2S,3R)-3-amino-2-hydroxy-4-phenyl-butanoyl]amino]-4-methyl-pentanoyl]amino]ethoxy]ethoxy]ethyl]anilino]-N-(6-methoxy-3-pyridyl)pyrimidine-4-carboxamide A mixture of 2-[N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]anilino]-N-(6-methoxy-3-pyridyl)pyrimidine-4-carboxamide hydrochloride (46%, 61 mg, 0.06 mmol), (2S)-2-[[(2S,3R)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenyl-butanoyl]amino]-4-methylpentanoic acid (51 mg, 0.12 mmol), and 1H-benzotriazole-1-ol hydrate (1:1) (42 mg, 0.27 mmol) in DMF (2 mL) was briefly sonicated, then cooled on ice, treated with DIPEA (65 μL, 0.37 mmol), and subsequently treated with EDC HCl (49 mg, 0.26 mmol). The mixture was stirred at 0°C for 12 minutes, then at room temperature over the weekend. The reaction mixture was then concentrated under vacuum, and the resulting oily residue was partitioned between toluene (10 mL) and water (5 mL). The layers were separated, and the aqueous phase was extracted with toluene (3 × 10 mL). The combined organic extract was successively washed with a solution of 10% citric acid (aq) (10 mL), a saturated solution of NaHCO3 (aq) (10 mL), and brine (10 mL), dried over MgSO4, filtered, concentrated under vacuum, and the product was obtained. The crude product was redissolved in MeOH (2 mL), treated with 4 M HCl in dioxane (373 μL), and stirred at room temperature for 2 hours. The mixture was retreated with 4 M HCl in dioxane (373 μL) and stirred at room temperature for a further 1.5 hours. Subsequently, the reaction mixture was concentrated under vacuum, the residue was dissolved in water (5 mL), treated with solid NaHCO3 (720 mg), and extracted with DCM (3 × 15 mL). The combined organic extracts were washed with brine (15 mL), dried over MgSO4, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by basic reverse-phase chromatography (C-18, 0-100% MeCN / water + 0.1% NH4OH). The clean fractions were combined, concentrated under vacuum, and freeze-dried overnight to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.56 (d, J = 4.8 Hz, 1H), 8.45 (d, J = 2.5 Hz, 1H), 8.18 (t, J = 5.6 Hz, 1H), 8.00 (dd, J = 8.9, 2.7 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 7.41 - 7.35 (m, 2H), 7.32 - 7.23 (m, 4H), 7.20 (d, J = 6.9 Hz, 2H), 7.19 - 7.15 (m, 1H), 6.88 (d, J = 8.8 Hz, 1H), 5.47 (d, J = 5.6 Hz, 1H), 4.28 (q, J = 8.9, 7.3 Hz, 3H), 3.85 (s, 3H), 3.74 (s, 1H), 3.65 (t, J = 5.8 Hz, 2H), 3.46 (dd, J = 5.9, 3.7 Hz, 2H), 3.39 (dd, J = 5.8, 3.6 Hz, 2H), 3.33 - 3.31 (m, 2H), 3.19 - 3.07 (m, 3H), 2.76 (dd, J = 13.2, 6.5 Hz, 1H), 2.52 (s, 1H), 1.64 - 1.52 (m, 1H), 1.46 (dtt, J = 22.1, 8.3, 4.2 Hz, 2H), 1.36 (d, J = 35.5 Hz, 2H), 0.84 (d, J = 6.6 Hz, 3H), 0.81 (d, J = 6.5 Hz, 3H). Tr(MET-uHPLC-AB-101) = 2.53 points, (ES + [M+H] + 743.2. 【0403】 Biotechnology [Example 21] Q46_RBAアッセイ Binding of W to mHTT. A radioligand binding assay was developed to screen for compounds that can effectively replace the radioligands described elsewhere (see, for example, U.S. Patent Application Publication 2017 / 0292150) from pre-formed polyQ46 or Exon1-polyQ46 (Q46_RBA) aggregates. 【0404】 Aggregation of polyQ peptides is initiated by cleaving the tag from the GST-polyQ46 or MBP-Exon1-polyQ46 fusion protein. The pre-formed aggregates are then subjected to binding to the aggregates. 3 The radiolabeled ligand was incubated with a competing compound. Readout was performed by MicroBeta measurement based on the scintillation of the radiolabeled ligand bound to the aggregate. Activity was indicated as follows: +++ for <100 nM, ++ for 100-500 nM, and + for >500 nM. 【0405】 [Table 19] TIFF0007872824000088.tif124165 【0406】 [Example 22] SPR assay A surface plasmon resonance (SPR) assay was developed to test the affinity (KD) of VHL or CRBN-based compounds to their respective recombinant ligase complexes / domains. 【0407】 The assay is based on surface plasmon resonance (SPR), which allows for the measurement of local refractive index changes due to changes in molecular mass on the gold tip surface and in the flow system when a binding event occurs. To detect binding between both partners, each E3 ligase is immobilized on the tip surface, while the test compound is flowed over the tip surface at a constant rate. Changes detected in the RU response indicate a binding event and are concentration-dependent. 【0408】 For SPR experiments, we used either a commercially available VHL complex exhibiting his tagging at the Cul2 subunit (Merck, 23-044, consisting of 5 units: VHL, elongin B, elongin C, Cul2, and Rbx1) or an internally prepared biotin-labeled mouse CRBN thalidomide-binding domain (mCRBN-TBD). These tags provide anchors for the capture process to either an NTA or streptavidin-coated chip surface (immobilization levels of 3,000–5,000 RU). Due to the somewhat complex structure of the VHL complex, further binding to the chip surface via amino coupling prevents any protein loss due to complex breakdown in the fluid system. 【0409】 The binding of the compound is detected, and the dissociation constant K of the test compound against the immobilized E3 ligase is determined. D To obtain the desired results, the concentration-response curves of the compounds were recorded. The compounds were tested at a maximum final concentration of 20 μM in assay buffer, typically at a 10pt dilution, and flowed onto the tip at 30 μL / min. Contact times for each cycle included 90 seconds for compound association and 200 seconds for dissociation. All test cycles were read out as sensorgrams referencing the sensor surface where the target protein was absent. 【0410】 In the table below, K d The values ​​are shown as follows: +++ for <100nM, ++ for 100~500nM, and + for >500nM. 【0411】 [Table 20] 【0412】 [Table 21] 【0413】 [Example 23] HTT degradation assay The compounds described herein are referred to as HTT-Exon1-polyQ nThe effectiveness of HTT reduction in human HeLa cells transiently overexpressing the protein was investigated. For the HTT degradation experiment, HeLa cells were transiently transfected with the pcDNA3.1(+)-hHTT-E1mixQn-EGFP plasmid for transient expression of HTT-Exon1 protein with different polyQ lengths (HTT-exon1-Q23 / 73 / 145-EGFP). Two hours after transfection, cells were treated with the test compound + DMSO control at seven concentrations ranging from 0.01 μM to 10 μM (final assay concentration). After 22 hours of incubation with the test compound, the cells were washed with 1×PBS and lysed on ice for 30 minutes in MSD lysis buffer (150mM NaCl, 20mM Tris pH 7.5, 1mM EDTA, 1mM EGTA, 1% Triton X-100, 1× phosphatase inhibitor cocktail 2, 1× phosphatase inhibitor cocktail 3, 1× protease inhibitor cocktail, 10mm NaF, 1mm PMSF). 【0414】 For the analysis of HTT protein levels using the Meso Scale Discovery (MSD) assay, MSD384-well plates were coated per well with 10 μL of each coating antibody (soluble mHTT-Assay 6:2B7 (5 μg / mL), agglutinating HTT-Assay 45:MW8, 4 μg / mL) in carbonate-bicarbonate coating buffer (15 mM Na2CO3, 35 mM NaHCO3, pH 9.6) at 4°C overnight. The plates were then washed three times with 35 μL of wash buffer per well (0.2% Tween-20 in PBS) and blocked with 35 μL of blocking buffer per well (2% probumin in PBS, 0.2% Tween-20) at room temperature for 1 hour with shaking. 【0415】 For mHTT aggregate-specific MSD assays, cell lysates were diluted to a final total protein concentration of 1 mg / ml in blocking buffer. For soluble mHTT MSD assays, cell lysates were first diluted to a total protein concentration of 0.2 mg / ml in lysis buffer, and then further diluted to a total protein concentration of 0.1 mg / ml in blocking buffer. 【0416】 After an additional washing step, 10 μL of sample per well was transferred to each well of an antibody-coated MSD plate and incubated at room temperature for 1 hour with shaking. After discarding the samples and performing three washing cycles with 35 μL each of wash buffer, 10 μL of primary SULFO-TAG(ST)-labeled detection antibody (soluble HTT: MW1 (5 μg / mL), aggregated HTT: 4C9 (1 μg / mL)) was added to each well and incubated at room temperature for 1 hour with shaking. After three washes with wash buffer, 35 μL of read buffer T (Meso Scale Discovery) containing a surfactant was added to each well. The plate was imaged on a Sector Imager 6000 (Meso Scale Discovery) according to the manufacturer's instructions and recommended settings for a 384-well plate. The obtained readouts were the MSD signal intensity for each well. Background values ​​were subtracted from each sample. Relative mHTT levels were normalized against a control sample containing only DMSO with the highest mHTT protein load. 【0417】 The decrease in solubility and aggregated mHTT Exon 1-Q73 levels by compound 1 was confirmed by MSD assay (Figures 1A, 1B, and 2). Compound 10, which has an inactive enantiomer ligase-binding domain, was found to be less active. 【0418】 Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which this invention pertains. 【0419】 The inventions described herein exemplary can be suitably put into practice in the absence of any elements or elements, limitations or limitations not specifically described herein. Therefore, terms such as “comprising,” “including,” and “containing” should be read broadly and without limitation. Furthermore, while the terms and expressions used herein are for illustrative purposes only and are not intended to exclude any equivalents or parts thereof of the characteristics indicated and described in the use of such terms and expressions, it should be recognized that various modifications are possible within the scope of the claimed inventions. 【0420】 All publications, patent applications, patents, and other references referred to herein are expressly incorporated by reference in whole to the same extent that each is incorporated by reference individually. In the event of any conflict, including definitions, this specification shall prevail. The following is one embodiment of the present invention. (1) Compound of formula (I) WL-ULM (I) or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or isotope-enriched analogs. (In the formula, W is a compound that targets mutant huntingtin protein (mHTT), L is a connecting portion which is either a bond or, in some cases, is replaced by B. ULM is a region that targets E3 ubiquitin ligase. B is the part that crosses the blood-brain barrier and / or enhances cell permeability. However, if the above compound [ka] (Provided that it is not the case.) (2) The compound described in (1), wherein the ULM is a moie double microchromosome 2 homolog (MDM2), apoptosis protein 1 cell inhibitor (cIAP1), cereblon (CRBN), or von Hippel-Lindou (VHL). (3) The compound described in (1), wherein ULM is the part that targets VHL ligase. (4) The compound described in (1), wherein the ULM is the part that targets cerebron ligase. (5) The compound described in (1), wherein ULM is the portion that targets the cell inhibitor of apoptosis protein 1 (cIAP1). (6) ULM [ka] (In the formula, R 40 is hydrogen or C 1~6 (It is alkyl.) A compound selected from (1). (7)R 40 The compound described in (6), wherein the hydrogen atom is hydrogen. (8) ULM 【change】 TIFF0007872824000094.tif99158 The compound described in (1). (9) W is a compound of formula (A) 【change】 (In the formula, The bond site of W to L-ULM is any substitutable atom in formula (A), L 1 Is -CH=CH- or L 1 It does not exist. R 1 is selected from phenyl or heteroaryl, and each of them is Cyano, Hello, Heteroaryl, Lower alkyl, Lower alkyl groups substituted with one or two substituents independently selected from lower alkoxy groups substituted with heteroaryl groups, -C(O)O- Lower alkyl, Hydroxyl, Lower alkynyl oxy, Lower alkoxys, and Hello, Heterocycloalkyl, Heteroaryl, Heteroaryls substituted with lower alkoxys, In some cases, the amino acids are substituted. Alkyls substituted with heteroaryls, and Alkyls substituted with lower alkoxys and heteroaryls Lower alkoxy substituted with one or two substituents independently selected from It is optionally replaced by one, two, or three elements independently selected from the above, or R 1 This is a phenyl compound substituted with two groups, which together with the carbon atom to which they are bonded form a heterocycloalkenyl ring, and the phenyl compound is Hello, Heteroaryls, and In some cases, the amino acids are substituted. They are further optionally s...

Claims

[Claim 1] Compound of formula (I) WL-ULM (I) or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or isotope-enriched analogs. (In the formula, W is a compound that targets mutant huntingtin protein (mHTT), selected from compounds of formula (B), formula (E), or formula (F). The compound of formula (B) 【Chemistry 1】 (In the formula, The bond site of W to L-ULM is any substitutable atom in formula (B), Z in equation (B) 1 , Z 2 , Z 3 and Z 4 It is selected independently of CH, R 5 is a heteroaryl, heterocycloalkyl or 【Chemistry 2】 And, L 3 is -O-, and L 4 is -(CR 8 R 9 ) p -, or L 3 -NR 10 - and L 4 is -C(O)-, L 5 It does not exist. R 6 It is selected from heteroaryls that are optionally substituted with one or two lower alkoxys, X 1 is O, Y 1 is N, R 10 It is hydrogen, Each R 7 These are independently selected from lower alkyl, lower alkoxy, and halo. Each R 8 It is selected independently of hydrogen, Each R 9 It is selected independently of hydrogen, n is either 0 or 1. p is 1) And, The compound of formula (E) 【Transformation 3】 (In the formula, The bond site of W to L-ULM is any substitutable atom in formula (E), J is C (=O), X in equation (E) 3 is N, Y in equation (E) 3 CH is, Z in equation (E) 5 CH is, In equation (E), Q is N, Each time it appears, R 23 This is independently selected from halo, lower alkoxy, hydroxy, aryl, heteroaryl, cycloalkoxy and lower alkyl, R 21 is hydrogen or a lower alkyl group. R 22 It is a heteroaryl, s is 0, 1, or 2. (r is either 1 or 2) And, The compound of formula (F) 【Chemistry 4】 (In the formula, r is 1, X in equation (F) 3 is S, Y in equation (F) 3 CH is, Z in equation (F) 5 CH is, In equation (F), Q is N, R 28 cyano and -NR 24 R 25 A heteroaryl compound optionally substituted with one, two, or three groups independently selected from the above, Each R 24 is independently selected from hydrogen or lower alkyl, and Each R 25 This is independently selected from hydrogen or a lower alkyl group. The wavy line represents the connection point of W to L in L-ULM. And, L is given by the following formula 【Transformation 5】 (In the formula, the dashed lines represent the connection points to W and ULM, f is an integer between 1 and 20. This is the connecting part, ULM 【Transformation 6】 (In the formula, R 40 is hydrogen or C 1～6 (It is alkyl.) (Selected from) [Claim 2] Compound of formula (I) WL-ULM (I) or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or isotope-enriched analogs. (In the formula, W is a compound of formula (C). 【Transformation 7】 (In the formula, The bond site of W to L-ULM is any substitutable atom in formula (C), X 2 is S, Y 2 is N, In equation (C), Z1, Z2, Z3, and Z4 are selected independently of CH. R 13 is an aryl that is optionally substituted with one or two optionally substituted aminos. L 6 does not exist. L 7 is (CH 2) q, R 14 is a lower alkyl group. Each R 15 is selected from lower alkyl, lower alkoxy, and halo. z is either 0 or 1. (q is 0) And, L is given by the following formula 【Transformation 8】 (In the formula, the dashed lines represent the connection points to W and ULM, f is an integer between 1 and 20. This is the connecting part, ULM 【Chemistry 9】 (In the formula, R 40 is hydrogen or C1-6 alkyl) (Selected from). [Claim 3] R 40 The compound according to claim 1, wherein the compound is hydrogen. [Claim 4] ULM 【Chemistry 10】 【change】 The compound according to claim 1. [Claim 5] The compound according to claim 1, wherein W is a compound of formula (B). [Claim 6] W is a compound of formula (B)(i)(a). 【Chemistry 11】 (In the equation, the dashed line represents the connection point of L-ULM to L.) The compound according to claim 5. [Claim 7] W is a compound of formula (B)(ii)(a). 【Chemistry 12】 (In the equation, the dashed line represents the connection point of L-ULM to L.) The compound according to claim 5. [Claim 8] R 5 The compound according to claim 5, wherein it is a heteroaryl compound. [Claim 9] R 5 but, 【Chemistry 13】 The compound according to claim 5. [Claim 10] R 5 The compound according to claim 5, wherein it is a heterocycloalkyl compound. [Claim 11] R 6 The compound according to claim 5, wherein is a 5-6 member heteroaryl, each of which is optionally substituted with one or two lower alkoxys. [Claim 12] W 【Chemistry 14】 (In the equation, the dashed line represents the connection point of L-ULM to L.) A compound according to claim 1, selected from the following. [Claim 13] The compound according to claim 1, wherein W is a compound of formula (E). [Claim 14] W is a compound of formula (E)(i). 【Chemistry 15】 (In the equation, the dashed line represents the connection point of L-ULM to L.) The compound according to claim 13. [Claim 15] R 21 The compound according to claim 13, wherein is hydrogen. [Claim 16] The compound according to claim 1, wherein W is a compound of formula (F). [Claim 17] R 28 However, cyano and -NR 24 R 25 The compound according to claim 16, which is a bicyclic heteroaryl optionally substituted with one, two, or three groups independently selected from the above. [Claim 18] R 28 However, cyano and -NR 24 R 25 The compound according to claim 16, which is a bicyclic heteroaryl optionally substituted with one or two groups independently selected from the above. 【Request Item 19】 【Table 1】 A compound selected from or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or isotopic enriched analog thereof. [Claim 20] A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, and a pharmaceutically acceptable excipient or carrier. [Claim 21] An agent for inducing the degradation of mHTT, comprising a therapeutically effective amount of the compound described in any one of claims 1 to 19 or the pharmaceutical composition described in claim 20. [Claim 22] An agent for treating Huntington's disease, comprising a therapeutically effective amount of the compound described in any one of claims 1 to 19 or the pharmaceutical composition described in claim 20.

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