Compounds for targeting mutant huntingtin protein and uses thereof

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 TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 62 / 810,213, filed February 25, 2019, which is incorporated by reference in its entirety.

[0002] The present invention relates generally to compounds that simultaneously bind to both mutant huntingtin protein (mHTT) and ubiquitin E3 ligase, and their use as therapeutic agents, e.g., in the treatment of diseases, e.g., 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 psychiatric impairments, as well as neurodegeneration and brain atrophy beginning in the striatum and cortex and spreading to other subcortical brain regions. Huntington's disease belongs to a family of neurodegenerative disorders caused by mutations in which an expanded CAG repeat sequence results in a long polyglutamine (polyQ) expansion in the encoded mutant protein. This family also includes dentatorubral-pallidoluysian atrophy (DRPLA), spinal-bulbar muscular atrophy (SBMA), and spinocerebellar ataxia (SCA). Apart from the polyQ repeat, the proteins involved are unrelated, and all result in distinctive patterns of degeneration despite being widely expressed in the central nervous system and peripheral tissues.

[0004] Although neuronal loss in numerous other brain regions has also been reported in HD, selective neurodegeneration of γ-aminobutyric acid-releasing spiny projection neurons in the striatum is prominent. In unaffected populations, the IT gene encoding the HD protein huntingtin (HTT protein) is expressed in HD. 15The number of CAG repeats in the gene varies from 6 to 35. More than 36 CAG repeats define the HD allele, resulting in the translation of a mutant huntingtin protein (mHTT) containing a longer polyQ expansion. 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 cases characterized by expansions of more than 60 repeats. HD has a global prevalence of 5 to 10 per 100,000 people, making it the most common inherited neurodegenerative disorder.

[0005] The HTT protein is a 348 kDa multidomain protein containing a polymorphic glutamine / proline-rich domain at its amino terminus. The longer polyQ domain of mHTT appears to induce a conformational change in the protein, which causes it to form intracellular aggregates that most often 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 associated with several organelles, including the Golgi apparatus, endoplasmic reticulum, and mitochondria. Summary of the Invention [Problem to be solved by the invention]

[0006] Because HD is caused by the expression of mHTT protein, reducing the expression of mHTT is an important therapeutic strategy. Reducing the amount of mHTT protein in the brain of HD patients is predicted to prevent cellular dysfunction, neurodegeneration, and alleviate disease symptoms. There remains a need for compounds that can effectively treat HD. [Means for solving the problem]

[0007] Provided herein are heterobifunctional molecules that simultaneously bind to both mHTT and ubiquitin E3 ligase.

[0008] In some embodiments, the compound of formula (I) WL-ULM (I) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or isotopically enriched analog thereof is provided herein. (In the formula, W is a compound that targets mutant huntingtin protein (mHTT); L is a bond or a linking moiety optionally substituted with B; ULM is a moiety that targets E3 ubiquitin ligases, B is a moiety that crosses the blood-brain barrier and / or enhances cell permeability).

[0009] Some embodiments provide pharmaceutical compositions comprising a compound as described herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or isotopically enriched analogue thereof, and a pharmaceutically acceptable excipient or carrier.

[0010] Also provided herein is a method of inducing degradation of mHTT, comprising administering a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or isotopically enriched analog thereof, or a pharmaceutical composition as described herein.

[0011] Also provided herein is a method of treating Huntington's disease, comprising administering a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or isotopically enriched analog thereof, or a pharmaceutical composition as described herein. [Brief explanation of the drawings]

[0012] [Figure 1A]Figure 1 shows HTT degradation of mHTT using compound 1 in HeLa cells transfected with various Exon1-Qn-EGFP constructs. Analysis by MSD assay for soluble mHTT (Figure 1A) and aggregated HTT (Figure 1B). [Figure 1B] Figure 1 shows HTT degradation of mHTT using compound 1 in HeLa cells transfected with various Exon1-Qn-EGFP constructs. Analysis by MSD assay for soluble mHTT (Figure 1A) and aggregated HTT (Figure 1B). [Figure 2] Figure 1 shows HTT degradation using compound 1 and compound 10 in HeLa cells transfected with Exon1-Q73-EGFP. Analysis by mHTT MSD assay. Blue circles refer to compound 1 and squares refer to compound 10, n=6 (3) independent experiments. Mean + / - SEM, BG=background. DETAILED DESCRIPTION OF THE INVENTION

[0013] definition The following description describes exemplary embodiments of the present technology, but it should be recognized that such description is not intended as a limitation on the scope of the present invention, but is instead provided as a description of exemplary embodiments.

[0014] As used herein, the following words, phrases, and symbols are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0015] A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent, for example, —CONH 2 is attached through a carbon atom.

[0016] As used herein, the terms "group," "radical," or "fragment" refer to a functional group or molecular fragment that is capable of attaching to a bond or to another molecular fragment.

[0017] If a range of values ​​is given (e.g. C 1~6 alkyl), including each value within the range and all intervening ranges. For example, "C 1~6 "Alkyl" refers to 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 Contains alkyl.

[0018] When a moiety is defined as optionally substituted, the moiety may be substituted by itself or as part of another moiety. For example, R x "C 1~6 Alkyl or OC 1~6 Alkyl, C 1~6 When "alkyl optionally substituted with halogen" is defined, C 1~6 Alkyl group alone and OC 1~6 C that forms part of an alkyl group 1~6 Both alkyls may be substituted with halogens.

[0019] The term "alkyl" includes straight-chain and branched-chain moieties 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 alkyl includes both straight-chain and branched-chain alkyls of 1 to 6 carbon atoms. Examples of C1-C6 alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylphenyl, and the like. When an alkyl residue having a specific number of carbons is named, it is intended to include all geometric isomers having that number of carbons; thus, for example, "butyl" is meant to include n-butyl, sec-butyl, isobutyl, and tert-butyl, and "propyl" includes n-propyl and isopropyl. "Lower alkyl" refers to an alkyl group having 1 to 6 carbons.

[0020] "Alkylene" refers to a divalent alkyl group as defined above. As used herein, alkylene refers to a divalent alkyl group having 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 alkylene).

[0021] "Heteroalkylene" refers to an alkylene group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatom 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 with the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NH-, -O-, -S-, -S(O)-, -S(O)2-, and the like. As used herein, heteroalkylene includes 1 to 8 carbon atoms, or 1 to 4 carbon atoms and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0022] By "alkoxy" is meant an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, and the like. Alkoxy groups will typically have 1 to 6 carbon atoms attached through an oxygen bridge. "Lower alkoxy" refers to an alkoxy group having 1 to 6 carbons. By "cycloalkoxy" is meant a cycloalkyl group similarly attached through an oxygen bridge.

[0023] "Alkenyl" refers to an unsaturated branched or straight-chain 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 atom from adjacent carbon atoms of the corresponding alkyl. Alkenyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-2-en-1-yl), and butenyl (e.g., but-1-en-1-yl, but-1-en-3-yl, but-3-en-1-yl). "Lower alkenyl" refers to an alkenyl group having 2 to 6 carbons.

[0024] "Alkenylene" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 8 carbon atoms (i.e., C 2~8 alkenylene), 2 to 6 carbon atoms (i.e., C 2~6 alkenylene), or 2 to 4 carbon atoms (i.e., C 2~4 It refers to an alkylene group having an alkyl group (alkenylene).

[0025] "Heteroalkenylene" refers to a heteroalkylene group containing at least one carbon-carbon double bond and having 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 the group --O-alkenyl, where alkenyl is as defined herein.

[0027] "Alkynyl" refers to an unsaturated branched or straight-chain 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 atoms from adjacent carbon atoms of the corresponding alkyl. Alkynyl groups include, but are not limited to, ethynyl, propynyl (e.g., prop-1-yn-1-yl, prop-2-yn-1-yl), and butynyl (e.g., but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl). "Lower alkynyl" refers to an alkynyl group having 2 to 6 carbons.

[0028] "Alkynylene" refers to an alkyl group containing at least one carbon-carbon triple bond and having 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 The term "alkynyl" also includes groups having one triple bond and one double bond.

[0029] "Heteroalkynylene" refers to a heteroalkylene group containing at least one carbon-carbon triple bond and having 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 group --O-alkynyl, where alkynyl is as defined 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., bicyclic, tricyclic). In some cases, both rings in a polycyclic aryl group are aromatic (e.g., naphthyl). In other cases, a polycyclic aryl group can include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to an aromatic ring, provided that the polycyclic aryl group is attached to the parent structure through an atom in the aromatic ring. Thus, a 1,2,3,4-tetrahydronaphthalen-5-yl group (where the moiety is attached to the parent structure through an aromatic carbon atom) would be considered an aryl group, while a 1,2,3,4-tetrahydronaphthalen-1-yl group (where the moiety is attached to the parent structure through a non-aromatic carbon atom) would not be considered an aryl group. Similarly, a 1,2,3,4-tetrahydroquinolin-8-yl group (where the moiety is attached to the parent structure through an aromatic carbon atom) is considered an aryl group, while a 1,2,3,4-tetrahydroquinolin-1-yl group (where the moiety is attached to the parent structure through 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 point of attachment (e.g., both quinolin-5-yl and quinolin-2-yl are heteroaryl groups). In some cases, aryl is phenyl or naphthyl. In certain cases, aryl is phenyl.

[0032] "Aralkyl" refers to "-alkylene-aryl."

[0033] "Arylene" refers to a divalent aryl group as defined above.

[0034] Divalent radicals formed from substituted benzene derivatives and having free valences on ring atoms are named substituted phenylene radicals. Divalent radicals derived from monovalent polycyclic hydrocarbon radicals whose names end in "-yl" by the removal of one hydrogen atom from the carbon atom having the free valence are named by adding "-ylidene" to the name of the corresponding monovalent radical; for example, a naphthyl group with two points of attachment is called a naphthylidene.

[0035] "Cycloalkyl" refers to a non-aromatic, fully saturated carbocyclic ring having the indicated number of carbon atoms, e.g., 3 to 10, or 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 bridged and caged ring groups (e.g., norbornane, bicyclo[2.2.2]octane). In addition, one ring of a polycyclic cycloalkyl group can be aromatic, provided that the polycyclic cycloalkyl group is attached to the parent structure through a non-aromatic carbon atom. For example, 1,2,3,4-tetrahydronaphthalen-1-yl (the moiety is attached to the parent structure through a non-aromatic carbon atom) is a cycloalkyl group, while 1,2,3,4-tetrahydronaphthalen-5-yl (the moiety is attached to the parent structure through an aromatic carbon atom) is not considered a cycloalkyl group. Examples of polycyclic cycloalkyl groups consisting of a cycloalkyl group fused to an aromatic ring are set forth below.

[0036] "Cycloalkylene" refers to a divalent cycloalkyl group as defined above.

[0037] "Cycloalkenyl" refers to a non-aromatic carbocyclic ring 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 atom from adjacent carbon atoms of the corresponding cycloalkyl. 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 can be aromatic, provided that the polycyclic alkenyl group is attached to the parent structure through a non-aromatic carbon atom. For example, inden-1-yl (the moiety is attached to the parent structure through a non-aromatic carbon atom) is considered a cycloalkenyl group, while inden-4-yl (the moiety is attached to the parent structure through an aromatic carbon atom) is not considered a cycloalkenyl group. Examples of polycyclic cycloalkenyl groups consisting of a cycloalkenyl group fused to an aromatic ring are set forth below.

[0038] The term "cycloalkoxy" refers to an --O-cycloalkyl, where cycloalkyl is as defined herein.

[0039] The term "cyano" refers to -CN.

[0040] The term "halo" includes fluoro, chloro, bromo, and iodo, and the term "halogen" includes fluorine, chlorine, bromine, and iodine.

[0041] "Haloalkyl" includes straight 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. When a haloalkyl group contains more than one halogen atom, the halogens can be the same (e.g., dichloromethyl) or different (e.g., chlorofluoromethyl). Examples of haloalkyl groups include, but are not limited to, 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" refers to an aromatic ring containing the indicated number of atoms (e.g., a 5- to 12-membered or 5- to 10-membered heteroaryl) composed of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S, 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, a heteroaryl group can be attached to the parent structure by a carbon or nitrogen atom, where 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 + -O - In addition, when sulfur is present in a heteroaryl ring, it may exist in an oxidized state (i.e., S + -O - or SO2). Heteroaryl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic).

[0043] In some cases, the heteroaryl group is a single ring. 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 the polycyclic heteroaryl group are aromatic. Examples include indole, isoindole, indazole, benzimidazole, benzotriazole, benzofuran, benzoxazole, benzisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzisothiazole, 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, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrrolo[3,4-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrazolo[3,4 ... 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, furo[2,3-b]pyridine, oxazolo[5,4- b]pyridine, isoxazolo[5,4-b]pyridine, [1,2,3]oxadiazolo[5,4-b]pyridine, furo[3,2-b]pyridine, oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine, [1,2,3]oxadiazolo[4,5-b]pyridine, furo[2,3-c]pyridine, oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine, [1,2,3]oxadiazolo[5,4-c]pyridine, furo[3,2-c]pyridine, oxazolo[4,5-c]pyridine, isoxazolo thiazolo[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]thiadiazolo[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., a cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl) fused to a heteroaryl ring, provided that the polycyclic heteroaryl group is attached to the parent structure through an atom in the aromatic ring. For example, a 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl group (where the moiety is attached to the parent structure through an aromatic carbon atom) would be considered a heteroaryl group, while a 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl group (where the moiety is attached to the parent structure through a non-aromatic carbon atom) would not be considered a heteroaryl group.

[0046] "Heteroaralkyl" refers to the group "-alkylene-heteroaryl".

[0047] "Heteroarylene" refers to a divalent heteroaryl group as defined above.

[0048] "Heteroaryloxy" refers to "-O-heteroaryl."

[0049] "Heterocycloalkyl" refers to a non-aromatic fully saturated ring (e.g., a 3- to 10-membered, or 3- to 7-membered heterocycloalkyl) having the indicated number of atoms, composed of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S, 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 oxiranyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.

[0051] When nitrogen is present in a heterocycloalkyl ring, it may 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, it may exist in an oxidized state (i.e., S + -O - or SO2-). Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide.

[0052] Additionally, one ring of a polycyclic heterocycloalkyl group can be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocycloalkyl group is attached to the parent structure through a non-aromatic carbon or nitrogen atom. For example, a 1,2,3,4-tetrahydroquinolin-1-yl group (where the moiety is attached to the parent structure through a non-aromatic nitrogen atom) is considered a heterocycloalkyl group, while a 1,2,3,4-tetrahydroquinolin-8-yl group (where the moiety is attached to the parent structure through an aromatic carbon atom) is not considered a heterocycloalkyl group.

[0053] "Heterocycloalkylene" refers to a divalent heterocycloalkyl group as defined above.

[0054] "Heterocycloalkenyl" refers to a non-aromatic ring (e.g., 3- to 10-membered, or 3- to 7-membered heterocycloalkyl) having the indicated number of atoms, composed of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S, with the remaining ring atoms being carbon, and having at least one double bond derived from the removal of one molecule of hydrogen from adjacent carbon atoms, adjacent nitrogen atoms, or adjacent carbon and nitrogen atoms of the corresponding heterocycloalkyl. Heterocycloalkenyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). When nitrogen is present in a heterocycloalkenyl ring, it can exist in an oxidized state (i.e., N), where the nature of the adjacent atoms and groups permits. + -O - In addition, when sulfur is present in a heterocycloalkenyl ring, it may 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). Additionally, one ring of a polycyclic heterocycloalkenyl group can be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocycloalkenyl group is attached to the parent structure through a non-aromatic carbon or nitrogen atom. For example, a 1,2-dihydroquinolin-1-yl group (where the moiety is attached to the parent structure through a non-aromatic nitrogen atom) is considered a heterocycloalkenyl group, while a 1,2-dihydroquinolin-8-yl group (where the moiety is attached to the parent structure through an aromatic carbon atom) is not considered a heterocycloalkenyl group.

[0055] The term "hydroxy" or "hydroxyl" refers to --OH.

[0056] "(Lower alkyl)thio" refers to the group "lower alkyl-S-".

[0057] "Oxo" refers to the (=O) or (O) group.

[0058] The terms "optionally" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as defined herein. With respect to any group containing one or more substituents, those of skill in the art will understand that such groups are not intended to induce any substitutions or substitution patterns that are sterically impractical, synthetically impractical, and / or inherently unstable.

[0059] The term "substituted," as used herein, means that any one or more hydrogens on the designated atom or group are replaced with one selected from the indicated group, provided that the normal valence of the designated atom is not exceeded. When a substituent is oxo (i.e., =0), two hydrogens on the atom are replaced. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to suggest a compound that is sufficiently robust to survive isolation from a reaction mixture and subsequent formulation as a pharmaceutical agent having at least practical utility. Unless otherwise specified, substituents are named in the core structure. For example, when (cycloalkyl)alkyl is included as a possible substituent, it is understood that the point of attachment of this substituent to the core structure is at the alkyl moiety.

[0060] The terms "substituted" alkyl (including without limitation C1-C4 alkyl), cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl, and heteroaryl, unless expressly defined otherwise, mean that one or more (e.g., up to five, e.g., up to three) hydrogen atoms have been replaced with -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 a C1-C4 alkyl group, -NR b R c , halo, cyano, oxo (as a substituent on heterocycloalkyl), 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 is selected from C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl; R b 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 to which they are attached form a heterocycloalkyl group; Each C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl optionally represents 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-C4 alkyl-NH2, -N(C1-C4 alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkylphenyl), -N(C1-C4 alkyl)(C1-C4 alkylheteroaryl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a heteroaryl substituent), -CO2H, -C(O)OC1-C4 alkyl, -CON(C1-C4 alkyl)(C 1-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 -NHSO(C1-C4 alkyl), -NHSO(aryl), -NHSO(heteroaryl), -NHSO(C1-C4 haloalkyl), -NHSO(aryl), -NHSO(heteroaryl), -NHSO(C1-C4 alkyl), -NHSO(phenyl), -NHSO(aryl), -NHSO(heteroaryl), and -NHSO(C1-C4 haloalkyl). " refers to alkyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl, and heteroaryl, each of which is substituted by a substituent independently selected from:

[0061] The term "amino" refers to the group --NH.sub.2.

[0062] The term "(alkyl)amino" refers to the group --NH(alkyl), where alkyl is as defined herein.

[0063] The term "di(alkyl)amino" refers to the group --N(alkyl)(alkyl), where alkyl is as defined herein.

[0064] The term "substituted amino" refers to -NHR d or -NR d R d Each R refers to a group. d are 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 are selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted acyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, alkoxycarbonyl, sulfinyl, and sulfonyl, and wherein one or more (e.g., up to 5, e.g., up to 3) hydrogen atoms are replaced by -R a , -OR b , —O(C1-C2 alkyl)O— (e.g., methylenedioxy-), —SR b , guanidine, guanidine in which one or more hydrogen atoms of guanidine are replaced by a lower alkyl group, -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 is selected from optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl; R b is selected from H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl; R c is selected from hydrogen and optionally substituted C1-C4 alkyl; Each optionally substituted group may be unsubstituted or selected from the group consisting of 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 alkylene heteroaryl), -N(C1-C4 alkyl)(C1-C4 alkyl heteroaryl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substituent on heteroaryl), -CO2H, -C(O)OC1-C4 alkyl, -CON(C1-C4 alkyl)(C1-C4 alkyl), -CONH(C1 ~C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(aryl), -N(C1-C4 alkyl)C(O)(heteroaryl), -C(O)C1-C4 alkyl, -C(O)C1-C6 aryl, -C(O)heteroaryl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, -SO -NHSO(C1-C4 alkyl), -SO(aryl), -SO(heteroaryl), -SO(C1-C4 haloalkyl), -SONH, -SONH(C1-C4 alkyl), -SONH(aryl), -SONH(heteroaryl), -NHSO(C1-C4 alkyl), -NHSO(aryl), -NHSO(heteroaryl), and -NHSO(C1-C4 haloalkyl) Each of these refers to an alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, each of which is substituted with a substituent independently selected from:

[0065] The term "substituted amino" also refers to -NR e R f R refers to the group e and R f together with the nitrogen to which they are attached form an 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" embraces groups of the formula --(C.dbd.O)(optionally substituted amino), where substituted amino is as described herein.

[0067] "Alkylaminocarbonyl" refers to -C(=O)((alkyl)amino), where (alkyl)amino is as described herein.

[0068] "Di(alkyl)aminocarbonyl" refers to -C(=O)(di(alkyl)amino), where di(alkyl)amino is as described herein.

[0069] The compounds described herein include, but are not limited to, their optical isomers, racemates, and other mixtures thereof. In these situations, single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of racemates can be accomplished, for example, by conventional methods, such as crystallization in the presence of a resolving agent, or chromatography, for example, using a chiral high-pressure liquid chromatography (HPLC) column. The term "isomers" refers to different compounds that have the same molecular formula. The term "stereoisomers" refers to isomers that differ only in the way their atoms are arranged in space. The term "enantiomers" refers to stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The symbol "(±)" may be used to indicate a racemic mixture where appropriate. The term "diastereoisomers" refers to stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified by the Cahn-Ingold-Prelog RS system. If a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be designated as either R or S. Resolved compounds whose absolute configuration is unknown can be designated as (+) or (-) depending on the direction (right-handed or left-handed) they rotate plane-polarized light at the wavelength of the sodium D line.

[0070] When the compounds described herein exist in various tautomeric forms, the term "compound" includes all tautomeric forms of the compound. Such compounds also include crystalline forms, including polymorphs and clathrates. Similarly, the term "salt" includes all tautomeric and crystalline forms of the compound. The term "tautomer" refers to structurally distinct isomers that interconvert via tautomerization. Tautomerization is a form of isomerization, includes prototropy or proton-shift tautomerization, and is considered a subset of acid-base chemistry. Prototropic or proton-shift tautomerization involves the migration of a proton, often accompanied by a change in bond order, swapping a single bond with an adjacent double bond. When tautomerization is possible (e.g., in solution), a chemical equilibrium of the tautomers can be achieved. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.

[0071] Pharmaceutically acceptable forms of the compounds listed herein include pharmaceutically acceptable salts and mixtures thereof. In some embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts.

[0072] "Pharmaceutically acceptable salts" include, but are not limited to, salts with inorganic acids, such as hydrochlorates, phosphates, diphosphates, hydrobromides, sulfates, sulfinates, nitrates, and the like; and salts with organic acids, such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, haloalkanoates, such as trifluoroacetate, and alkanoates, such as acetate, HOOC(CH2) where n is 0-4. n-COOH and other salts are included. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium. In addition, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly 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, according to conventional procedures for preparing acid addition salts from the parent compound. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts.

[0073] Any compound or structure depicted herein is intended to represent unlabeled forms of the compound as well as "isotopically enriched analogs." Isotopically enriched forms of compounds may also be referred to as "labeled." Isotopically enriched analogs have the structures depicted herein except that one or more atoms are enriched with an isotope having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, 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. Generally, isotopically enriched analogs include compounds having any isotopic enrichment above the natural abundance of the isotope (e.g., at the Earth's surface). Various isotopically labeled compounds, such as radioactive isotopes, e.g., 3 H, 18 F, 11 C.13 C and 14 Those incorporating C are included in the present invention. 18 F, 3 H or 11 Compounds labeled with C may be useful in metabolism studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substance tissue distribution assays, or in radiation treatment of patients.

[0074] The term "isotopically enriched analog" includes "deuterated analogs" of the compounds described herein in which one or more hydrogens, e.g., hydrogens on carbon atoms, have been replaced with deuterium. Such compounds can exhibit increased metabolic resistance and thus can be useful for increasing the half-life of any compound when administered to mammals, particularly humans. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds can be synthesized by means well known in the art, for example, by utilizing starting materials in which one or more hydrogens have been replaced with deuterium.

[0075] Deuterium-labeled or -substituted compounds of the present invention can have improved DMPK (drug metabolism and pharmacokinetics) properties related to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, can result in certain therapeutic benefits due to greater metabolic stability, such as increased in vivo half-life, reduced dosing requirements, and / or improved therapeutic index. Isotopically labeled compounds of the present invention are generally prepared by carrying out the procedures disclosed in the schemes or examples and preparations described hereinafter by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents. When compounds are described as deuterated analogs, the compounds 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 the present invention, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen and its isotopes at their natural abundance.

[0077] As used herein, the term "huntingtin protein" or "HTT protein" as a β-amyloid aggregate refers to the protein encoded by the human huntingtin gene (HTT gene), which is located at position 16.3 on the short (p) arm of chromosome 4. More precisely, the IT15 gene, which encodes the HTT protein, is located on chromosome 4 at base pair 3,076,407 to base pair 3,245,686.

[0078] The term "β-amyloid aggregates," as used herein, refers to insoluble fibrillar amyloids comprising misfolded β-amyloid protein molecules.

[0079] The term "HTT protein aggregates," as used herein, refers to insoluble fibrillar amyloids comprising misfolded HTT protein molecules.

[0080] The term "mutant huntingtin protein" or "mHTT protein" refers to a polyglutamine-expanded version of the HTT protein produced by the expansion of a CAG repeat in the huntingtin gene. This mutant form of the HTT protein is prone to misfolding and aggregate formation.

[0081] The term "compound that targets mutant huntingtin protein" refers to a compound that is capable of binding 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 them for degradation. E3 ubiquitin ligases, either alone or in complex with E2 ubiquitin-conjugating enzymes, are responsible for the transfer of ubiquitin to target proteins. Generally, ubiquitin ligases are involved in polyubiquitination (marking a protein for degradation by the proteasome), such that a second ubiquitin binds to the first, a third ubiquitin binds to the second, and so on.

[0083] The term "E3 ubiquitin ligase targeting moiety" refers to a molecule that can bind to and / or recruit an 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 "cereblon ligase targeting moiety" refers to a molecule that can bind to and / or recruit cereblon (CRBN).

[0086] The term "cellular inhibitor of apoptosis protein 1 targeting moiety" refers to a molecule that can bind to and / or recruit cellular 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 in the brain, the blood-spinal cord barrier in the spinal cord, and the blood-retinal barrier in the retina are continuous capillary barriers in the central nervous system and are collectively referred to herein as the blood-brain barrier or BBB. The BBB also encompasses the blood-CSF barrier (choroid plexus), which is composed of ependymal cells rather than capillary endothelial cells.

[0088] The term "blood-brain barrier-penetrating and / or cell-permeability-enhancing moiety" refers to a molecule or macromolecule that can be transported across the BBB and / or exhibits increased ability to cross cell membranes. Transport across the BBB can be achieved by various mechanisms known in the art (e.g., transmembrane diffusion, saturable transporters, adsorptive endocytosis, and extracellular pathways). Transport across cell membranes is also known in the art (e.g., active or passive transport mechanisms). In some embodiments, a molecule or macromolecule can assist in the delivery of an active agent across the BBB and / or cell membrane. Non-limiting examples of moieties that cross the blood-brain barrier and / or enhance cell permeability are as described herein.

[0089] The term "substitutable atom" refers to an atom that can be further substituted with groups or moieties as described herein, and in some embodiments, such substitutions cause the compounds described herein to retain activity. It will be understood by those of skill in the art that such groups or moieties are not intended to induce any substitutions or substitution patterns that are sterically impractical, synthetically impractical, and / or inherently unstable.

[0090] compound Compounds that simultaneously bind to both mHTT and ubiquitin E3 ligase are provided herein, and it is contemplated that such compounds promote the ubiquitination and degradation of mHTT.

[0091] In some embodiments, it is contemplated that simultaneous binding of the compounds described herein to both mHTT and ubiquitin E3 ligase results in ternary complex formation, followed by transfer of multiple ubiquitin molecules to mHTT, and following dissociation or degradation of the complex, the polyubiquitinated mHTT is recognized and degraded by the proteasome.

[0092] Some embodiments include a compound of formula (I) WL-ULM (I) or 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 bond or a linking moiety optionally substituted with B; ULM is a moiety that targets E3 ubiquitin ligases, B is a moiety that crosses the blood-brain barrier and / or enhances cell permeability).

[0093] Some embodiments include a compound of formula (I) WL-ULM (I) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or isotopically enriched analog thereof. (In the formula, W is a compound that targets mutant huntingtin protein (mHTT); L is a bond or a linking moiety optionally substituted with B; ULM is a moiety that targets E3 ubiquitin ligases, B is a moiety that crosses the blood-brain barrier and / or enhances cell permeability).

[0094] In some embodiments, the compound of formula (I)

[0095] [ka] Not TIFF2025032084000002.tif26141.

[0096] In some embodiments, the compound of Formula (I) comprises one linking moiety optionally substituted with B.

[0097] Some embodiments provide deuterated analogs of compounds of formula (I).

[0098] In some embodiments, each of W, L, and ULM in a compound of Formula (I) can be bonded to any available substituent to form a compound of Formula (I). In some embodiments, a substitutable atom of W is bonded (e.g., covalently bonded) to a substitutable atom of L. In some embodiments, a substitutable atom of L is bonded (e.g., covalently bonded) to a substitutable atom of ULM.

[0099] In some embodiments, the compound of formula (I) WL-ULM (I) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or isotopically enriched analog thereof is provided herein. (In the formula, L is a linking moiety optionally substituted with B; ULM is

[0100] [ka] TIFF2025032084000004.tif52162, W is (i) a compound of formula (A)

[0101] [ka] wherein the point of attachment of W to L-ULM is any substitutable atom of formula (A), (ii) a compound of formula (B)

[0102] [ka] wherein the point of attachment of W to L-ULM is any substitutable atom of formula (B), or (iii) a compound of formula (E)

[0103] [ka] wherein the point of attachment of W to L-ULM is any substitutable atom of formula (E). and The variables of formulas (A), (B) and (E) are as described herein).

[0104] Typical W part In some embodiments, W is a compound that binds to mutant huntingtin protein (mHTT).

[0105] It is contemplated that even after W is conjugated to L-ULM, the compound of formula (I) retains 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 prior to conjugation to L-ULM.

[0106] In some embodiments, W is a compound of formula (A)

[0107] [ka] (In the formula, The point of attachment of W to L-ULM is any substitutable atom of formula (A); L1 is -CH=CH- or L1 is absent; R1 is selected from phenyl or heteroaryl, each of which is Cyano, Hello, heteroaryl, lower alkyl, Lower alkoxy substituted with heteroaryl lower alkyl substituted with 1 or 2 substituents independently selected from —C(O)O-lower alkyl, hydroxyl, lower alkynyloxy, lower alkoxy, and Hello, heterocycloalkyl, heteroaryl, heteroaryl substituted with lower alkoxy; optionally substituted amino, alkyl substituted with heteroaryl, and Alkyl substituted with heteroaryl substituted with lower alkoxy lower alkoxy substituted with 1 or 2 substituents independently selected from and optionally substituted with 1, 2, or 3 groups independently selected from or R1 is a phenyl substituted with two groups which, together with the carbon atom to which they are attached, form a heterocycloalkenyl ring, and the phenyl is Hello, heteroaryl, and optionally substituted amino and optionally further substituted with a substituent selected from L2 is -N(R4)- or L2 is absent; R2 is hydrogen, lower alkyl, and Lower alkyl substituted with lower alkoxy, amino, (alkyl)amino, (dialkyl)amino or hydroxy is selected from Each time it appears, R3 Hello, Cyano, lower alkoxy, lower alkyl optionally substituted with amino, (alkyl)amino or di(alkyl)amino, and Ethynyl optionally substituted with tri(alkyl)silyl are independently selected from R4 is hydrogen or lower alkyl; m is 0, 1 or 2 is.

[0108] In some embodiments, W is a compound of formula (B)

[0109] [ka] (In the formula, the point of attachment of W to L-ULM is any substitutable atom of formula (B); Z1, Z2, Z3, and Z4 are independently selected from CH and N, with the proviso that at least two of Z1, Z2, Z3, and Z4 are CH; R5 is heteroaryl, heterocycloalkenyl, or heterocycloalkyl, 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; or R5 is phenyl optionally substituted with one or two groups independently selected from cyano, heteroaryl, halo, phenoxy, benzyloxy, heteroaryl, amino, lower alkyl optionally substituted with (alkyl)amino or di(alkyl)amino, lower alkoxy, optionally substituted amino, di(alkyl)aminocarbonyl, alkylaminocarbonyl, and aminocarbonyl; L3 is -O- and L4 is -(CR8R9) p -or-(CR8R9) p -O-, or L3-NR 10 -, and L4 is -C(O)- or -(R8R9) p -or- L3-NR 10 - and L4 is -C(O)(O)(R8R9) p -or- L3-NR 10- and L4 is -C(O)(R8R9) p (O)-, or L3-NR 10 - and L4 is -C(O)(R8R9) p -or- L3-NR 10 - and L4 is -C(O)CR8=CR9-; or L3 is -C(O)- and L4 is -NR 10 -or- L3 is -(R8R9) p - and L4 is -NR 10 -, -C(O)- or -O-; or L3 is absent and L4 is absent, or L3 together with L4 is -CH=CH-, -C≡C- or heterocyclylene; L5 is -CH=CH- or L5 is absent; 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, heteroaryloxy substituted with lower alkyl; hydroxyl, lower alkenyloxy, 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 optionally substituted with one or two groups selected from X1 is NR 12 , O or S; Y1 is CR 12 or N, R 10 is hydrogen or lower alkyl, R 12 is hydrogen, halo, cyano, or lower alkyl; each R7 is independently selected from lower alkyl, lower alkoxy, and halo; R 11 is lower alkyl, each R8 is independently selected from hydrogen, hydroxyl, trifluoromethyl, and lower alkyl; each R9 is independently selected from hydrogen and lower alkyl; n is 0 or 1, p is 0, 1 or 2 is.

[0110] In some embodiments, W is a compound of formula (B)(i)

[0111] [ka] (wherein the wavy line represents the point of attachment to L of L-ULM).

[0112] In some embodiments, W is a compound of formula (B)(i)(a)

[0113] [ka] (wherein the wavy line represents the point of attachment to L of L-ULM).

[0114] In some embodiments, W is a compound of formula (B)(ii)

[0115] [ka] (wherein the wavy line represents the point of attachment to L of L-ULM).

[0116] In some embodiments, W is a compound of formula (B)(ii)(a)

[0117] [ka] (wherein the wavy line represents the point of attachment to L of L-ULM).

[0118] In some embodiments, R5 is heteroaryl optionally substituted with 1 or 2 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.

[0119] In some embodiments, R5 is heterocycloalkenyl optionally substituted with 1 or 2 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.

[0120] In some embodiments, R5 is heterocycloalkyl optionally substituted with 1 or 2 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.

[0121] In some embodiments, R6 is a 5-6 membered 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 lower alkoxy substituted with halo; 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 point of attachment of W to L-ULM is any substitutable atom of formula (C); X2 is (CR 16 =CR 16 ), O, NH or S, Y2 is CR 16 or N, Each R 16 are independently selected from hydrogen, halo, cyano, and lower alkyl; Z1, Z2, Z3, and Z4 are independently selected from CH and N, with the proviso that at least two of Z1, Z2, Z3, and Z4 are CH; R 13 is aryl, heteroaryl, or heterocycloalkyl, each of which is optionally substituted with one or two groups independently selected from alkynyl, heteroaryl, cyano, optionally substituted amino, halo, and lower alkyl optionally substituted with optionally substituted amino; L6 is absent or C(O)O, O or NR 17 and R 17 is hydrogen or lower alkyl, L7 is (CH2) q and R 14is 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 together with any intervening atoms to form a 5- to 7-membered heterocycloalkyl ring; z is 0 or 1; q is 0, 1 or 2 is.

[0124] In some embodiments, W is a compound of formula (D)

[0125] [ka] (In the formula, the point of attachment of W to L-ULM is any substitutable atom of formula (D); Z1, Z2, Z3, and Z4 are independently selected from CH and N, with the proviso that at least two of Z1, Z2, Z3, and Z4 are CH; R 18 is 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 lower alkyl substituted with optionally substituted amino; L8 is O or NR 21 and R 21 is hydrogen or lower alkyl, L9 is (CH2) x and R 19 is hydrogen, aryl, aryl substituted with hydroxyl or lower alkoxy, heteroaryl, and heteroaryl substituted with hydroxyl or lower alkoxy; Each R 20is independently selected from lower alkyl, lower alkoxy, halo, and oxo (as substituents on the heterocycloalkyl ring); x is 0, 1 or 2; y is 0 or 1) is.

[0126] In some embodiments, W is a compound of formula (E)

[0127] [ka] (In the formula, the point of attachment of W to L-ULM is any substitutable atom of formula (E); J is C(=O) or -CH2-; X3 is S or N; Y3 is CH or N; Z5 is CH or N; Q is N or S; Each time it appears, R 23 is independently selected from halo, lower alkoxy, hydroxy, aryl, heteroaryl, cycloalkoxy, and lower alkyl, and lower alkoxy, cycloalkoxy, lower alkyl, aryl, or heteroaryl is independently selected from lower alkoxy, alkenyl, -NR 24 R 25 each optionally substituted with 1, 2, or 3 groups independently selected from halo and heteroaryl optionally substituted with 1 to 3 lower alkoxy; R 21 is hydrogen or lower alkyl, R 22 is alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, or heteroaralkyl, each of which is selected from the group consisting of hydroxy, lower alkoxy, or lower alkoxy optionally substituted with halo, lower alkyl optionally substituted with halo, halo, heteroaryl, -(CH) t NR 24 R 25 , oxo, cyano, and -C(O)-NR 24 R25 optionally substituted with 1, 2, or 3 groups independently selected from R 21 and R 22 together with the nitrogen to which they are attached, represent hydroxy, lower alkoxy, lower alkyl, halo, and —C(O)—NR 24 R 25 forming a heterocycloalkyl ring optionally substituted with 1, 2 or 3 groups independently selected from t is 0, 1 or 2; Each R 24 are independently selected from hydrogen or lower alkyl; Each R 25 are independently selected from hydrogen or lower alkyl, or R 24 and R 25 together with the nitrogen to which they are attached, represent hydroxy, lower alkoxy, lower alkyl, halo, or —C(O)—NR 26 R 27 forming a heterocycloalkyl ring optionally substituted with 1, 2 or 3 groups independently selected from Each R 26 are independently hydrogen or lower alkyl; Each R 27 are independently hydrogen or lower alkyl; s is 0, 1 or 2; r is 1 or 2) is.

[0128] In some embodiments, W is a compound of formula (E)(i)

[0129] [ka] (wherein the wavy line represents the point of attachment to L of L-ULM).

[0130] In some embodiments, R 21 is hydrogen and R 22is aryl, aralkyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, or heteroaralkyl, each of which is selected from the group consisting of hydroxy, lower alkoxy, or lower alkoxy optionally substituted with halo, lower alkyl optionally substituted with halo, halo, heteroaryl, -(CH) t NR 24 R 25 , oxo, cyano, and -C(O)-NR 24 R 25 and optionally substituted with 1, 2, or 3 groups independently selected from:

[0131] In some embodiments, W is a compound of formula (F)

[0132] [ka] (In the formula, X3 is S or N; Y3 is CH or N; Z5 is CH or N; Q is N or S; R 28 is cyano, lower alkoxy, lower alkenyl, -NR 24 R 25 , halo, and heteroaryl optionally substituted with 1 to 3 lower alkoxy; Each R 24 are independently selected from hydrogen or lower alkyl; Each R 25 are independently selected from hydrogen or lower alkyl, or R 24 and R 25 together with the nitrogen to which they are attached, represent hydroxy, lower alkoxy, lower alkyl, halo, or —C(O)—NR 26 R 27 forming a heterocycloalkyl ring optionally substituted with 1, 2 or 3 groups independently selected from Each R 26are independently hydrogen or lower alkyl; Each R 27 are independently hydrogen or lower alkyl; The wavy line represents the attachment point of W to L in L-ULM. is.

[0133] In some embodiments, R 28 is cyano, lower alkoxy, lower alkenyl, -NR 24 R 25 and bicyclic heteroaryl optionally substituted with 1, 2, or 3 groups independently selected from heteroaryl optionally substituted with 1 to 3 lower alkoxy groups.

[0134] In some embodiments, R 28 -cyano and -NR 24 R 25 is a bicyclic heteroaryl optionally substituted with one or two groups independently selected from:

[0135] In some embodiments, W is attached to L of L-ULM by any substitutable atom; 2-(5-Fluoro-1-benzofuran-2-yl)-N-methylimidazo[1,2-a]pyridin-3-amine; 2-(5-Methoxy-1-benzofuran-2-yl)-N-methylimidazo[1,2-a]pyridin-3-amine; 6-Fluoro-2-(5-methoxy-1-benzofuran-2-yl)-N-methylimidazo[1,2-a]pyridin-3-amine; 7-Fluoro-2-(5-methoxy-1-benzofuran-2-yl)-N-methylimidazo[1,2-a]pyridin-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]pyridin-2-yl]-1-benzofuran-5-ol; 2-(5-Methoxy-1-benzofuran-2-yl)-N-(2-methoxyethyl)imidazo[1,2-a]pyridin-3-amine; 2-[7-fluoro-3-(methylamino)imidazo[1,2-a]pyridin-2-yl]-1-benzofuran-5-ol; 2-{3-[(2-hydroxyethyl)amino]imidazo[1,2-a]pyridin-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]pyridin-3-amine; 3-(Methylamino)-2-[3-(pyridin-3-ylmethoxy)phenyl]imidazo[1,2-a]pyridine-7-carbonitrile; 3-(Methylamino)-2-[4-(pyridin-3-ylmethoxy)phenyl]imidazo[1,2-a]pyridine-7-carbonitrile; 7-chloro-2-(5-methoxy-1-benzofuran-2-yl)-N-methylimidazo[1,2-a]pyridin-3-amine; 7-Bromo-2-(5-methoxy-1-benzofuran-2-yl)-N-methylimidazo[1,2-a]pyridin-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-(pyrazin-2-yl)phenyl]imidazo[1,2-a]pyridine-7-carbonitrile; 3-(Methylamino)-2-[4-(pyrazin-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-carbonitrile; 2-(1-benzofuran-5-yl)-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 3-(Methylamino)-2-[4-(prop-2-yn-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-methoxypyrazin-2-yl)methoxy]phenyl}-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 2-{5-[(5-methoxypyrazin-2-yl)methoxy]pyridin-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-benzodiazol-2-yl)-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 2-(6-Methoxy-1,3-benzothiazol-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-benzodiazol-2-yl)-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 2-(5-Methoxy-1-benzofuran-2-yl)imidazo[1,2-a]pyridine-7-carbonitrile; 2-(6-Methoxy-1-methyl-1H-1,3-benzodiazol-2-yl)-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 3-(Methylamino)-2-[5-(pyridin-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-carbonitrile; 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-carbonitrile; 3-(Methylamino)-2-{4-[(pyridin-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-Butyl 2-[7-cyano-3-(methylamino)imidazo[1,2-a]pyridin-2-yl]-4H,5H,6H,7H-furo[3,2-c]pyridine-5-carboxylate; 7-(aminomethyl)-2-(5-methoxy-1-benzofuran-2-yl)-N-methylimidazo[1,2-a]pyridin-3-amine; 3-(Methylamino)-2-{3-[(pyridin-3-ylmethoxy)methyl]phenyl}imidazo[1,2-a]pyridine-7-carbonitrile; 2-{4-[(5-methoxypyrazin-2-yl)methoxy]phenyl}-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 2-{6-[(5-methoxypyrazin-2-yl)methoxy]pyridin-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]pyridin-3-amine; 7-ethynyl-2-(5-methoxy-1-benzofuran-2-yl)-N-methylimidazo[1,2-a]pyridin-3-amine; 2-(4-{[(5-methoxypyridin-2-yl)methyl]amino}phenyl)-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; 2-(4-{5H,6H-imidazo[2,1-b][1,3]thiazol-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-methoxypyridin-2-yl)methoxy]pyrazin-2-yl}-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile The compound is selected from

[0136] In some embodiments, W is attached to L of L-ULM by any substitutable atom; tert-butyl 4-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]piperazine-1-carboxylate, 4-Methoxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]benzamide; 4-Methoxy-N-[2-(pyridin-4-yl)-1,3-benzoxazol-5-yl]benzamide; N-[(4-methoxyphenyl)methyl]-2-(pyridin-3-yl)-1,3-benzoxazol-5-amine; 2-(3-bromopyridin-4-yl)-6-[2-(morpholin-4-yl)ethoxy]-1,3-benzothiazole; 5-Methoxy-N-[2-(3-methylphenyl)-1,3-benzoxazol-5-yl]pyridine-2-carboxamide; 6-Methoxy-N-[2-(3-methylphenyl)-1,3-benzoxazol-5-yl]pyridine-3-carboxamide; 2-Methoxy-N-[2-(3-methylphenyl)-1,3-benzoxazol-5-yl]pyrimidine-5-carboxamide; 5-Methoxy-N-[2-(3-methylphenyl)-1,3-benzoxazol-5-yl]pyrazine-2-carboxamide; 4-Methoxy-N-[2-(3-methylphenyl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]benzamide; 5-(4-methoxyphenyl)-2-(pyridin-3-yl)-1,3-benzoxazole; N-(4-methoxyphenyl)-2-(pyridin-3-yl)-1,3-benzoxazol-5-amine; 2-(pyridin-3-yl)-N-{[1,2,4]triazolo[4,3-a]pyridin-3-yl}-1,3-benzoxazol-5-amine; 2-(pyridin-3-yl)-N-(pyrimidin-4-yl)-1,3-benzoxazol-5-amine; 2-(pyridin-3-yl)-N-(pyrimidin-2-yl)-1,3-benzoxazol-5-amine; 5-(5-methoxypyridin-2-yl)-2-(pyridin-3-yl)-1,3-benzoxazole; 5-(2-Methoxypyrimidin-5-yl)-2-(pyridin-3-yl)-1,3-benzoxazole; 5-(5-methoxypyrimidin-2-yl)-2-(pyridin-3-yl)-1,3-benzoxazole; 5-(6-Methoxypyridazin-3-yl)-2-(pyridin-3-yl)-1,3-benzoxazole; 5-(5-methoxypyrazin-2-yl)-2-(pyridin-3-yl)-1,3-benzoxazole; 1-methyl-4-[5-(pyrimidin-5-ylmethoxy)-1-benzofuran-2-yl]-1H-pyrazole-3-carbonitrile; 4-[5-(pyrimidin-5-ylmethoxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile; 4-{5-[(5-methoxypyridin-2-yl)methoxy]-1-benzofuran-2-yl}pyridine-3-carbonitrile; 4-{5-[(5-methoxypyridin-2-yl)methoxy]-1-benzofuran-2-yl}pyridine; 4-{5-[(1-methyl-1H-imidazol-4-yl)methoxy]-1-benzofuran-2-yl}pyridine-3-carbonitrile; 4-{5-[(1-methyl-1H-imidazol-2-yl)methoxy]-1-benzofuran-2-yl}pyridine-3-carbonitrile; 5-Methoxy-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-2,3-dihydro-1H-isoindol-1-one; 3-{6-[(E)-2-(4-methoxyphenyl)ethenyl]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine; 4-[5-(pyridin-3-yloxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile; 6-methoxy-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-1,2,3,4-tetrahydroisoquinolin-1-one; Dimethyl({3-[4-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)phenoxy]propyl})amine; 5-[(1-methyl-1H-pyrazol-4-yl)methoxy]-2-(pyridin-3-yl)-1,3-benzoxazole; 5-[(4-methoxyphenyl)methoxy]-2-(pyridin-3-yl)-1,3-benzoxazole; 5-[(3-methoxyphenyl)methoxy]-2-(pyridin-3-yl)-1,3-benzoxazole; 5-[(5-methoxypyridin-2-yl)methoxy]-2-(pyridin-3-yl)-1,3-benzoxazole; 2-(pyridin-3-yl)-5-(pyridin-3-ylmethoxy)-1,3-benzoxazole; 5-{5H,6H-Imidazo[2,1-b][1,3]thiazol-3-ylmethoxy}-2-(pyridin-3-yl)-1,3-benzoxazole; 1-(pyridin-2-yl)-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]ethan-1-ol; 1-(pyridin-2-yl)-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]ethan-1-one; 6-Methoxy-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-1,2-dihydroisoquinolin-1-one; 2-(pyridin-3-yl)-N-[2,2,2-trifluoro-1-(4-methoxyphenyl)ethyl]-[1,3]oxazolo[5,4-b]pyridin-6-amine; 3-{6-[2-(4-methoxyphenyl)ethynyl]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine; 3-{6-[(Z)-2-(4-methoxyphenyl)ethenyl]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine; 5-Methoxy-2-[2-(pyridin-3-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]-2,3-dihydro-1H-isoindol-1-one; 5-[(5-methoxypyrazin-2-yl)methoxy]-2-(pyridin-3-yl)-1,3-benzoxazole; 3-Methoxy-6-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-7-one; 2-(pyridin-3-yl)-6-(pyridin-3-ylmethoxy)-1,3-benzoxazole; 3-{6-[2-(pyridin-3-yl)ethynyl]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine; 5-{[(5-methoxypyridin-2-yl)oxy]methyl}-2-(pyridin-3-yl)-1,3-benzoxazole; 4-[5-(pyridin-3-ylmethoxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile; 4-{5-[(1-methyl-1H-pyrazol-4-yl)methoxy]-1-benzofuran-2-yl}pyridine-3-carbonitrile; 3-[5-(pyridin-3-ylmethoxy)-1-benzofuran-2-yl]pyridine-4-carbonitrile; 3-{5-[(1-methyl-1H-pyrazol-4-yl)methoxy]-1-benzofuran-2-yl}pyridine-4-carbonitrile; 3-{6-[1-(5-methoxypyridin-2-yl)ethoxy]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine; 4-{5-[(5-methoxypyrazin-2-yl)methoxy]-1-benzofuran-2-yl}pyridine-3-carbonitrile; 6-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)pyridin-3-ol; 5-{[5-(prop-2-en-1-yloxy)pyrazin-2-yl]methoxy}-2-(pyridin-3-yl)-1,3-benzoxazole; 5-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)-1,2-dihydropyrazin-2-one; 1-methyl-5-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)-1,2-dihydropyrazin-2-one; 5-[4-(5-methoxypyrimidin-2-yl)piperazin-1-yl]-2-(pyridin-3-yl)-1,3-benzoxazole; 3-{6-[(5-methoxypyridin-2-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine; 5-(1-methyl-1H-pyrazol-4-yl)-2-(pyridin-3-yl)-1,3-benzoxazole; 3-{6-[(6-methoxypyridin-3-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine; 5-[(5-methoxypyridin-2-yl)methoxy]-2-(pyridin-4-yl)-1,3-benzoxazole; [(3-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}phenyl)methyl]dimethylamine; 5-[(5-methoxypyridin-2-yl)methoxy]-2-(1-methyl-1H-pyrazol-4-yl)-1,3-benzoxazole; 5-[(5-methoxypyridin-2-yl)methoxy]-2-(pyrazin-2-yl)-1,3-benzoxazole; 5-[(5-methoxypyridin-2-yl)methoxy]-2-(1-methylpiperidin-4-yl)-1,3-benzoxazole; 5-[(5-methoxypyridin-2-yl)methoxy]-2-(1,3-thiazol-5-yl)-1,3-benzoxazole; 5-[2-(pyridin-2-yloxy)ethoxy]-2-(pyridin-3-yl)-1,3-benzoxazole; 4-[5-(1H-pyrazol-4-ylmethoxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile; 3-{[(2-{5H,6H-imidazo[2,1-b][1,3]thiazol-3-yl}-1-benzofuran-5-yl)oxy]methyl}pyridine; 2-(3-fluoroazetidin-1-yl)-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole; 2-{3H,4H,5H,6H,7H-Imidazo[4,5-c]pyridin-5-yl}-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole; 5-[(5-methoxypyridin-2-yl)methoxy]-2-{2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}-1,3-benzoxazole; 2-{5H,6H,7H,8H-Imidazo[1,5-a]pyrazin-7-yl}-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole; 5-[(5-methoxypyridin-2-yl)methoxy]-2-{5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl}-1,3-benzoxazole; 7-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-5,6,7,8-tetrahydro-1,7-naphthyridine; 2-(1H-imidazol-1-yl)-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole; 2-{5H,6H,7H,8H-Imidazo[1,2-a]pyrazin-7-yl}-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole; 4-(5-{[1-(2-methoxyethyl)-1H-pyrazol-4-yl]methoxy}-1-benzofuran-2-yl)pyridine-3-carbonitrile; 2-[5-(2-methoxyethoxy)pyridin-3-yl]-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole; N-(5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}pyridin-2-yl)acetamide; 5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}pyridin-2-amine; Methyl({[4-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)phenyl]methyl})amine; 4-(5-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]methoxy}-1-benzofuran-2-yl)pyridine-3-carbonitrile; Dimethyl({2-[4-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)phenoxy]ethyl})amine; 5-{[5-(2-methoxyethoxy)pyridin-2-yl]methoxy}-2-(pyridin-3-yl)-1,3-benzoxazole; 4-[5-({1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}methoxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile; 5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-N-methylpyridin-2-amine; 3-{[(2-{2-bromo-5H,6H-imidazo[2,1-b][1,3]thiazol-3-yl}-1-benzofuran-5-yl)oxy]methyl}pyridine; 5-[(5-methoxypyrazin-2-yl)methoxy]-1-methyl-2-(pyridin-3-yl)-1H-1,3-benzodiazole; 6-[(5-methoxypyrazin-2-yl)methoxy]-1-methyl-2-(pyridin-3-yl)-1H-1,3-benzodiazole; 5-[(5-methoxypyrazin-2-yl)methoxy]-2-(pyridin-3-yl)-1H-1,3-benzodiazole; 5-[(5-methoxypyridin-2-yl)methoxy]-2-(piperazin-1-yl)-1,3-benzoxazole; N-methyl-6-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)pyridin-3-amine; 3-[5-(pyridin-3-ylmethoxy)-1-benzofuran-2-yl]-5H,6H-imidazo[2,1-b][1,3]thiazole-2-carbonitrile; 5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-N-methylpyridine-2-carboxamide; 5-[(5-methoxypyridin-2-yl)methoxy]-2-(1-methyl-1H-imidazol-4-yl)-1,3-benzoxazole; 5-Methoxy-N-{[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]methyl}pyridin-2-amine; 4-(5-{5H,6H-imidazo[2,1-b][1,3]thiazol-3-ylmethoxy}-1-benzofuran-2-yl)pyridine-3-carbonitrile; 5-({5-[2-(morpholin-4-yl)ethoxy]pyridin-2-yl}methoxy)-2-(pyridin-3-yl)-1,3-benzoxazole; 2-Bromo-6-{5-[(5-methoxypyridin-2-yl)methoxy]-1-benzofuran-2-yl}benzonitrile; 4-{[2-(4-chlorophenyl)-1,3-benzoxazol-5-yl]carbamoyl}phenyl acetate; 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-benzoxazol-5-yl]benzamide; 3-Methoxy-N-[2-(4-methoxyphenyl)-1,3-benzoxazol-5-yl]benzamide; 3-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}pyridin-1-ium-1-olate; 2-phenoxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]acetamide; N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-1-benzofuran-2-carboxamide; N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-6-(trifluoromethyl)pyridine-3-carboxamide; N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]quinoxaline-2-carboxamide; 6-phenoxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]pyridine-3-carboxamide; N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-2H-1,3-benzodioxole-5-carboxamide; 3-(benzyloxy)-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]benzamide; 3-phenoxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]benzamide; N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]quinoline-2-carboxamide; N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-2,3-dihydro-1-benzofuran-2-carboxamide; 5-Methyl-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]pyridine-3-carboxamide; N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]quinoxaline-6-carboxamide; (2E)-3-(4-methoxyphenyl)-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]prop-2-enamide; 5-Methoxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]pyridine-2-carboxamide; 3-cyano-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]benzamide; 4-(Methylsulfanyl)-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]benzamide; benzyl N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]carbamate, 5-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]pyrazin-2-ol; 5-[(5-methoxypyridin-2-yl)methoxy]-2-(pyrimidin-5-yl)-1,3-benzoxazole; 2-(2,3-Dihydro-1-benzofuran-2-yl)-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole; 2-[(2R)-2,3-Dihydro-1-benzofuran-2-yl]-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole; 2-[(2S)-2,3-Dihydro-1-benzofuran-2-yl]-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole; 5-[5-(2-methoxyethoxy)pyrimidin-2-yl]-2-(pyridin-3-yl)-1,3-benzoxazole; 5-[(5-methoxypyridin-2-yl)methoxy]-2-(5-methylpyridin-3-yl)-1,3-benzoxazole; 5-[(5-methoxypyridin-2-yl)methoxy]-2-(2-methylpyridin-4-yl)-1,3-benzoxazole; 5-[(5-methoxypyridin-2-yl)methoxy]-2-(3-phenoxyphenyl)-1,3-benzoxazole; 6-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-2-methyl-2,3-dihydropyridazin-3-one; 5-[(5-methoxypyridin-2-yl)methoxy]-2-(pyridazin-3-yl)-1,3-benzoxazole; 5-[(5-methoxypyridin-2-yl)methoxy]-2-(pyridazin-4-yl)-1,3-benzoxazole; 5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-1,2-dihydropyridin-2-one; 5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-1-methyl-1,2-dihydropyridin-2-one; 5-phenyl-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-1,3,4-oxadiazole-2-carboxamide; 5-[(5-methoxypyridin-2-yl)methoxy]-2-(pyrimidin-4-yl)-1,3-benzoxazole; 5-[(5-bromopyridin-2-yl)methoxy]-2-(pyridin-3-yl)-1,3-benzoxazole; 5-(pyridin-2-ylmethoxy)-2-(pyridin-3-yl)-1,3-benzoxazole; N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-1-benzofuran-5-carboxamide; 2-Phenyl-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]pyrimidine-5-carboxamide; N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-4-(pyrimidin-2-yl)benzamide; 1-Methyl-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-1H-pyrazole-4-carboxamide; 4-[(6-methylpyrazin-2-yl)oxy]-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]benzamide; 4-(phenoxymethyl)-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]benzamide; 2-phenoxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]pyridine-3-carboxamide; 4-cyano-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]benzamide; 6-Methoxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]pyridine-2-carboxamide; 2-Methyl-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]pyridine-4-carboxamide; 3-Methoxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]pyridine-2-carboxamide; 4-Methoxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]pyridine-2-carboxamide; 4-Hydroxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]pyridine-2-carboxamide; 3-Methoxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-1,2-oxazole-5-carboxamide; 5-Methoxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]pyridine-3-carboxamide; 6-({[2-(1-methyl-1H-pyrazol-4-yl)-1,3-benzoxazol-5-yl]oxy}methyl)pyridin-3-ol; 5-[(5-methoxypyrazin-2-yl)methoxy]-2-(1-methyl-1H-pyrazol-4-yl)-1,3-benzoxazole; 2-Methoxy-5-({[2-(1-methyl-1H-pyrazol-4-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]oxy}methyl)pyrazine; 3-{6-[(5-bromopyridin-2-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine; 3-Methoxy-6-({[2-(pyridin-3-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]oxy}methyl)pyridazine; 3-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}benzonitrile; 4-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}benzonitrile; 5-(1-methyl-1H-pyrazol-4-yl)-2-({[2-(pyridin-3-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]oxy}methyl)pyridine; 3-Methoxy-5-({[2-(pyridin-3-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]oxy}methyl)pyridine; 4-Methoxy-2-({[2-(pyridin-3-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]oxy}methyl)pyridine; 2-({[2-(1-methyl-1H-pyrazol-4-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]oxy}methyl)pyrazine; [(3-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}phenyl)methyl](methyl)amine; (5-Methoxypyridin-2-yl)methyl N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]carbamate; 2-(5-methoxypyridin-2-yl)-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole; 2-(1-benzofuran-2-yl)-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole; 5-[(5-methoxypyridin-2-yl)methoxy]-2-[6-(trifluoromethyl)pyridin-3-yl]-1,3-benzoxazole; 2-(1-benzofuran-5-yl)-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole; 2-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}quinoline; 2-[3-(benzyloxy)phenyl]-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole; 5-[(5-methoxypyridin-2-yl)methoxy]-2-[4-(pyrimidin-2-yl)phenyl]-1,3-benzoxazole; 2-[(E)-2-(4-methoxyphenyl)ethenyl]-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole; 5-Methoxy-2-({[2-(pyridin-3-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]oxy}methyl)pyrimidine; 6-({[2-(1-methyl-1H-pyrazol-4-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]oxy}methyl)pyridin-3-amine; 5-{5-[(5-hydroxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-N-methylpyridine-2-carboxamide; 6-{6-[(5-methoxypyridin-2-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridin-2-yl}-2-methyl-2,3-dihydropyridazin-3-one; 2-methyl-6-({[2-(pyridin-3-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]oxy}methyl)-2,3-dihydropyridazin-3-one; 2-{6-[(5-methoxypyridin-2-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyrazine; 5-{6-[(5-methoxypyridin-2-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridin-2-yl}-N-methylpyridine-2-carboxamide; 5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-1-methyl-1,2-dihydropyrazin-2-one; 6-(6-{[5-(2-fluoroethoxy)pyridin-2-yl]methoxy}-[1,3]oxazolo[5,4-b]pyridin-2-yl)-2-methyl-2,3-dihydropyridazin-3-one; 5-Methoxy-2-({[2-(pyridin-3-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]oxy}methyl)pyridin-1-ium-1-olate; 3-{6-[(5-methoxy-1-oxidopyridin-1-ium-2-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridin-1-ium-1-olate; 5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-2-(methylcarbamoyl)pyridin-1-ium-1-olate; (5-Hydroxypyridin-2-yl)methyl N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]carbamate; 5-Methoxy-N-[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazol-5-yl]pyridine-2-carboxamide; 5-Methoxy-N-[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazol-5-yl]pyridine-3-carboxamide; 4-Methoxy-N-[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazol-5-yl]pyridine-2-carboxamide; 1-Methyl-N-[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazol-5-yl]-6-oxo-1,6-dihydropyridazine-3-carboxamide; [(5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}pyridin-3-yl)methyl](methyl)amine; 6-{5-[(5-hydroxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-2-methyl-2,3-dihydropyridazin-3-one; and N-(5-methoxypyridin-3-yl)-2-(pyridin-3-yl)-1,3-benzoxazole-5-carboxamide The compound is selected from

[0137] In some embodiments, W is attached to L of L-ULM by any substitutable atom; 6-Methoxy-2-(pyridin-3-yl)-1,3-benzoxazole; [2-(pyridin-3-yl)-1,3-benzoxazol-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-methoxynaphthalen-2-yl)pyridine-3-carbonitrile; 6-Methoxy-2-(2-methoxyphenyl)-1,3-benzothiazole; 4-(6-methoxy-1,3-benzothiazol-2-yl)benzonitrile; 4-(6-methoxy-1H-1,3-benzodiazol-2-yl)pyridine-3-carbonitrile; 6-Methoxy-2-[3-(1H-pyrazol-5-yl)pyridin-4-yl]-1,3-benzothiazole; 4-(6-Methoxy-1,3-benzothiazol-2-yl)-N-methylpyridin-3-amine; 4-(6-methoxyquinolin-2-yl)pyridine-3-carbonitrile; 4-(6-methoxy-1,3-benzothiazol-2-yl)pyridine-3-carbonitrile; 4-(5-methoxy-1-benzofuran-2-yl)pyridine-3-carbonitrile; N-[6-(5-methoxy-1-benzofuran-2-yl)pyridin-2-yl]acetamide; 6-(5-methoxy-1-benzofuran-2-yl)pyridine-3-carbonitrile; 4-(1,3-benzothiazol-2-yl)pyridine-3-carbonitrile; 2-(6-methoxy-1,3-benzothiazol-2-yl)benzonitrile; 2-(3-bromopyridin-4-yl)-6-methoxy-1,3-benzothiazole; 2-(3-bromopyridin-4-yl)-1,3-benzothiazol-6-ol; 2-(3-bromopyridin-2-yl)-6-methoxy-1,3-benzothiazole; 2-(6-methoxy-1,3-benzothiazol-2-yl)pyridine-3-carbonitrile; 2-(3-fluoropyridin-4-yl)-6-methoxy-1,3-benzothiazole; 4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]pyridine-3-carbonitrile; 4-(6-methoxy-1,3-benzothiazol-2-yl)pyridine-2-carbonitrile; 2-(6-methoxy-1,3-benzoxazol-2-yl)benzonitrile; N-[4-(6-methoxy-1,3-benzothiazol-2-yl)pyridin-3-yl]acetamide; 2-(3-bromopyridin-4-yl)-6-(2-fluoroethoxy)-1,3-benzothiazole; 4-[6-(2-fluoroethoxy)-1,3-benzothiazol-2-yl]pyridine-3-carbonitrile; 4-(5-methoxy-1,3-benzothiazol-2-yl)pyridine-3-carbonitrile; 4-[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]pyridine-3-carbonitrile; 4-[5-(2-fluoroethoxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile; 3-(6-methoxy-1,3-benzothiazol-2-yl)pyridine-4-carbonitrile; 5-Bromo-3-{5-bromofuro[2,3-b]pyridin-2-yl}-1,2-dihydropyridin-2-one; 2-{5-methoxyfuro[2,3-c]pyridin-2-yl}benzonitrile; 2-{5-bromofuro[2,3-b]pyridin-2-yl}benzonitrile; 2-{5-methoxyfuro[2,3-b]pyridin-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-methoxyfuro[2,3-c]pyridin-2-yl}pyridine-3-carbonitrile; 4-{6-methoxyfuro[3,2-b]pyridin-2-yl}pyridine-3-carbonitrile; 4-(3-bromo-5-methoxy-1-benzofuran-2-yl)pyridine; 5-Methoxy-2-(pyridin-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-methoxyfuro[2,3-d]pyrimidin-6-yl}benzonitrile; 4-(6-methoxy-1,3-benzoxazol-2-yl)pyridine-3-carbonitrile; 3-(5-Methoxy-1-benzofuran-2-yl)-5H,6H-imidazo[2,1-b][1,3]thiazole-2-carbonitrile; 3-ethynyl-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-benzoxazol-5-amine; 2-(pyridin-3-yl)-1,3-benzoxazol-5-amine; 2-(pyridin-4-yl)-1,3-benzoxazol-5-amine; and 2-(3-methylphenyl)-[1,3]oxazolo[5,4-b]pyridin-6-amine The compound is selected from

[0138] In some embodiments, W is attached to L of L-ULM by any substitutable atom; 2-(5-Methoxy-2,3-dihydro-1H-isoindol-2-yl)pyridine-3-carbonitrile; 2-{5-[(5-methoxypyridin-2-yl)methoxy]-2,3-dihydro-1H-isoindol-2-yl}pyridine-3-carbonitrile; 2-[5-(pyrimidin-5-ylmethoxy)-2,3-dihydro-1H-isoindol-2-yl]pyridine-3-carbonitrile; 4-{5-[(5-methoxypyridin-2-yl)methoxy]-2,3-dihydro-1H-isoindol-2-yl}pyridine-3-carbonitrile; 4-(5-Methoxy-2,3-dihydro-1H-isoindol-2-yl)pyrimidine-5-carbonitrile; 4-{5-[(5-methoxypyridin-2-yl)methoxy]-2,3-dihydro-1H-isoindol-2-yl}pyrimidine-5-carbonitrile; 4-{5-[(5-hydroxypyridin-2-yl)methoxy]-2,3-dihydro-1H-isoindol-2-yl}pyridine-3-carbonitrile; 4-(5-Methoxy-2,3-dihydro-1H-isoindol-2-yl)pyridine-3-carbonitrile; 4-[5-(pyrimidin-5-ylmethoxy)-2,3-dihydro-1H-isoindol-2-yl]pyridine-3-carbonitrile; 5-[(5-methoxypyrazin-2-yl)methoxy]-2-(pyridin-4-yl)-2,3-dihydro-1H-isoindole; 4-[5-(benzyloxy)-2,3-dihydro-1H-isoindol-2-yl]pyrimidine-5-carbonitrile; 4-{5-[(5-hydroxypyridin-2-yl)methoxy]-2,3-dihydro-1H-isoindol-2-yl}pyrimidine-5-carbonitrile; 6-{5-[(5-methoxypyridin-2-yl)methoxy]-2,3-dihydro-1H-isoindol-2-yl}-2-methyl-2,3-dihydropyridazin-3-one; and 5-[(5-methoxypyridin-2-yl)methoxy]-2-(pyridin-4-yl)-2,3-dihydro-1H-isoindol-1-one The compound is selected from

[0139] In some embodiments, W is attached to L of L-ULM by any substitutable atom; 10-Methoxy-N-(pyridin-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-methoxypyridin-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-(pyridin-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-(pyridin-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-methoxypyridin-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-methoxypyridin-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-fluoropyridin-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-(pyridin-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-methoxypyridin-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-pyrazol-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-fluoropyridin-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-(pyridin-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-methoxypyridin-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)pyridin-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-methylpyridin-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-dihydropyridazin-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-methylpyrimidin-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-imidazol-1-yl)pyridin-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-(pyrimidin-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-dihydropyridin-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-(pyridin-3-yl)pyridin-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-dihydropyridazin-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-(pyridin-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)pyridin-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-methoxypyridin-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-dihydropyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 ]Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide; N-(pyridin-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-cyanopyridin-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-methoxypyridin-4-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7]Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide; N-(5,6-dimethoxypyridin-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-triazatricyclo[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-methoxypyridin-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-methoxypyridin-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-imidazol-1-yl)pyridin-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-cyanopyridin-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-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-(3-cyano-2-methoxypyridin-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-methoxypyridin-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-methoxypyridin-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-methoxypyridin-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-(pyridin-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-(pyrazin-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-pentaen-4-amido}pyridin-1-ium-1-olate; 10-(2-Fluoroethoxy)-N-(pyridin-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)pyridin-3-amine; 10-[(5-methoxypyridin-2-yl)methoxy]-N-(5-methoxypyridin-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-dihydropyridin-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-methoxypyridin-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-(prop-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-methoxypyridin-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-dihydropyridazin-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-methylpyrimidin-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-dihydropyrimidin-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-methoxypyridin-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-dihydropyridazin-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-methoxypyridin-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-methoxypyridin-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-methoxypyridin-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-methoxypyridin-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)pyridin-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)pyridin-3-yl]-1,8,10-triazatricyclo[7.4.0.0 2,7 ]Trideca-2(7),3,5,8,10,12-hexaene-11-carboxamide The compound is selected from

[0140] In some embodiments, W is

[0141] [ka] (wherein the wavy line represents the point of attachment to L in L-ULM) is selected from.

[0142] Representative ULM parts In some embodiments, ULM is a moiety that recognizes ubiquitin pathway proteins. In some embodiments, the ubiquitin pathway proteins are E3 ubiquitin ligases. In some embodiments, ULM is a moiety that binds to E3 ubiquitin ligases. In some embodiments, ULM is an E3 ligase ubiquitin recruiter that targets E3 ubiquitin ligases.

[0143] Representative ULMs are known in the art (e.g., WO2018 / 102067, which is incorporated herein by reference in its entirety).

[0144] In some embodiments, the ULM is a molecule that binds to mouse double minute two homolog (MDM2), cellular inhibitor of apoptosis protein 1 (cIAP1), cereblon (CRBN), or von Hippel-Lindau (VHL). Such representative molecules are known in the art (e.g., Gu et al., BioEssays, April 2018, Vol. 40(4):e170024, incorporated herein by reference in its entirety).

[0145] In some embodiments, the ULM is a compound of formula (VIII)

[0146] [ka] (a is 1, 2 or 3, X A and X B are each independently a bond, O, or NR B , C.R. B R C , C=O, C=S, SO and SO2; R B and R C are each independently hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6 alkoxy; Each R A H, halo, OH and C 1~3 independently selected from alkyl, W A is -T(NR D1 R D2 ), optionally substituted -T(NR D1 R D2 )X C , -T-aryl, optionally substituted T-heteroaryl, optionally substituted -T-heterocycle, optionally substituted -NR D -T-aryl, optionally substituted -NR D -T-heteroaryl or -NR D-T-heterocycle, where T is X A is covalently bonded to X C is C=O, R D , R D1 or R D2 and R D , R D1 and R D2 each independently represents a C optionally substituted with hydrogen, 1 to 3 halo, or OH; 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 )SO2, T is a bond or a C optionally substituted with 1 to 5 halo or OH groups. 1~12 alkyl or optionally substituted amino acid side chains, W B is optionally substituted -NR D4 -T-aryl, optionally substituted -NR D4 -T-heteroaryl or -NR D4 -T-heterocycle, -NR D4 is X B is covalently bonded to R D4 is hydrogen or C 1~3 is alkyl, ULM is bonded to WL at any substitutable atom of ULM and L).

[0147] In some embodiments, ULM has the formula

[0148] [ka] is a compound of (W C, CH2, CHR E , C=O, SO2, NH or N-alkyl; each X D is independently selected from O, S, and H2; Y A is CH2, -C=CR F , NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O or S; Z A is X D and Z A are O, S, or H2, provided that both cannot be H2; G A and G B are each independently H, R F alkyl optionally substituted with OH, R F OCOOR E , R F OCONR E R G , R F -CH2-heterocyclyl optionally substituted with, and R F benzyl optionally substituted with Q A , Q B , Q C and Q D are each independently 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 G, aryl, 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 , Halo, -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 are each independently a bond, H, N,N-oxide, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, or —C(O)R H wherein alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted; R H is hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; Z B are functional groups or atoms, one of which is optionally modified so as to be covalently linked to the remainder of the compound of formula (I).

[0149] In some embodiments, Z B is the bond connecting ULM and WL in formula (I).

[0150] In some embodiments, the ULM is a moiety that targets mouse double minute 2 homolog (MDM2), cellular inhibitor of apoptosis protein 1 (cIAP1), cereblon (CRBN), or von Hippel-Lindau (VHL).

[0151] In some embodiments, ULM is a moiety that targets VHL ligase.

[0152] In some embodiments, ULM is a moiety that targets cereblon ligase.

[0153] In some embodiments, ULM is a moiety that targets cellular inhibitor of apoptosis protein 1 (cIAP1).

[0154] In some embodiments, ULM is

[0155] [ka] (In the formula, R 40 is hydrogen or C 1~6 alkyl) is selected from.

[0156] In some embodiments, R 40 is hydrogen.

[0157] In some embodiments, ULM is

[0158] [ka] The file is TIFF2025032084000024.tif88161.

[0159] Typical L part In some embodiments, L is a bond.

[0160] In some embodiments, L is a linking moiety optionally substituted with B.

[0161] In some embodiments, the linking moiety is alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene; Each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene can optionally include arylene, heteroarylene, cycloalkylene, or heterocycloalkylene; Further, each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene may be substituted with oxo, halo, C 1~4 Alkyl, C 1~4 Alkoxy and C 1~4 and optionally substituted independently with 1 to 5 substituents independently selected from haloalkyl.

[0162] In some embodiments, the linking moiety has the formula -G1-((CH2) a -G2) c -(CH2) b -G3- (In the formula, Each of G1, G2 and G3 independently represents a bond, -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, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene, and each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene is selected from the group consisting of oxo, halo, C 1~4 Alkyl, C 1~4 Alkoxy and C 1~4 is optionally substituted independently with 1 to 5 substituents independently selected from haloalkyl; Each R 28 are independently hydrogen, C 1~4 Alkyl, C 1~4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; R 29 is C 1~4 Alkyl, C 1~4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; a and b are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8; c is an integer between 0 and 20, The linking moiety is on a substitutable atom: (-G4-(CH2) d -G5-) e -B is sometimes replaced by G 4 and G 5 each independently represents a bond, -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, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene, and each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene is selected from the group consisting of oxo, halo, C 1~4 Alkyl, C 1~4 Alkoxy and C 1~4 is optionally substituted independently with 1 to 5 substituents independently selected from haloalkyl; d and e are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8. It is of the type.

[0163] In some embodiments, the linking moiety has the formula -G1-((CH2) a -G2) c -(CH2) b -G3- (In the formula, Each of G1, G2 and G3 independently represents a bond, -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, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene, and each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene is selected from the group consisting of oxo, halo, C 1~4 Alkyl, C 1~4 Alkoxy and C 1~4is optionally substituted independently with 1 to 5 substituents independently selected from haloalkyl; Each R 28 are independently hydrogen, C 1~4 Alkyl, C 1~4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; R 29 is C 1~4 Alkyl, C 1~4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; a and b are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8; c is an integer between 0 and 20 It is of the type.

[0164] In some embodiments, the linking moiety has the formula (-G1-(CH2) a -G2-(CH2) b -G3-) c (In the formula, Each of G1, G2 and G3 independently represents a bond, -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, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene, and each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene is selected from the group consisting of oxo, halo, C 1~4 Alkyl, C 1~4 Alkoxy and C 1~4is optionally substituted independently with 1 to 5 substituents independently selected from haloalkyl; Each R 28 independently, C 1~4 Alkyl, C 1~4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; R 29 is C 1~4 Alkyl, C 1~4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; a, b, and c are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8; The linking moiety is on a substitutable atom: (-G4-(CH2) d -G5-) e -B is sometimes replaced by G 4 and G 5 each independently represents a bond, -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, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene, and each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene is selected from the group consisting of oxo, halo, C 1~4 Alkyl, C 1~4 Alkoxy and C 1~4 is optionally substituted independently with 1 to 5 substituents independently selected from haloalkyl; d and e are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8. It is of the type.

[0165] In some embodiments, the linking moiety has the formula (-G1-(CH2) a -G2-(CH2) b -G3-) c (In the formula, Each of G1, G2 and G3 independently represents a bond, -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, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene, and each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene is selected from the group consisting of oxo, halo, C 1~4 Alkyl, C 1~4 Alkoxy and C 1~4 is optionally substituted independently with 1 to 5 substituents independently selected from haloalkyl; Each R 28 independently, C 1~4 Alkyl, C 1~4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; R 29 is C 1~4 Alkyl, C 1~4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; a, b, and c are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8. It is of the type.

[0166] In some embodiments, the linking moiety has the formula

[0167] [ka] (wherein the wavy lines represent points of attachment to W and ULM; f is an integer between 1 and 20, Any substitutable atom may be further optionally substituted with L-B, where L is any linking moiety as described herein. It is of the type.

[0168] In some embodiments, the linking moiety has the formula

[0169] [ka] (wherein the wavy lines represent points of attachment to W and ULM; f is an integer between 1 and 20 It is of the type.

[0170] Typical B part In some embodiments, L is a linking moiety optionally substituted with B, and B is a moiety that crosses the blood-brain barrier.

[0171] In some embodiments, the blood-brain barrier penetrating moiety is a molecule or macromolecule that can penetrate the blood-brain barrier by targeting a receptor for transport across the blood-brain barrier, including those known in the art.

[0172] In some embodiments, B is a carrier peptide, cholesterol, or a carrier peptide conjugated to cholesterol (eg, by a linking moiety or covalent bond as described herein).

[0173] In some embodiments, the carrier peptide is a peptide having about 5 to 35 residues and capable of crossing a cell membrane. Exemplary 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, Nipah virus envelope (env.) HR region conjugated to cholesterol, Newcastle disease virus conjugated to cholesterol, or measles virus peptide conjugated to cholesterol.

[0175] Peptide sequences for representative B moieties are provided in Table 1 below.

[0176] [Table 1]

[0177] Representative compounds In some embodiments, there is provided a compound selected from Table 2, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof. In some embodiments, there is provided a compound selected from Table 2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or isotopically enriched analog thereof.

[0178] [Table 2] TIFF2025032084000029.tif239164TIFF2025032084000030.tif230164TIFF2025032084000031.tif241164 TIFF2025032084000032.tif234164TIFF2025032084000033.tif240164TIFF2025032084000034.tif214164 TIFF2025032084000035.tif228165TIFF2025032084000036.tif236166TIFF2025032084000037.tif255166 TIFF2025032084000038.tif225167TIFF2025032084000039.tif253168TIFF2025032084000040.tif205168

[0179] Treatment Methods and Uses "Treatment" or "treating" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results may include one or more of the following: a) preventing a disease or condition (e.g., reducing one or more symptoms caused by a disease or condition and / or reducing the severity of the disease or condition), b) delaying or halting the onset of one or more clinical symptoms associated with a disease or condition (e.g., stabilizing the disease or condition, preventing or slowing the worsening or progression of the disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of the disease or condition), and / or c) palliating the disease, i.e., causing a reduction in clinical symptoms (e.g., ameliorating the disease state, causing partial or complete remission of the disease or condition, enhancing the effectiveness of other drug therapies, slowing the progression of the disease, increasing quality of life, and / or prolonging survival).

[0180] "Prevention" or "preventing" means any treatment of a disease or condition that keeps the clinical symptoms of the disease or condition from manifesting. The compounds, in some embodiments, can be administered to subjects (including humans) who are at risk or have a family history of the disease or condition.

[0181] "Subject" refers to an animal, e.g., a mammal (including a human), that has been or is the object of treatment, observation, or experiment. The methods described herein may be useful in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0182] The term "therapeutically effective amount" or "effective amount" of a compound described herein or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof means an amount sufficient to effect treatment when administered to a subject to provide a therapeutic benefit, e.g., amelioration of symptoms or delay of disease progression. For example, a therapeutically effective amount can be an amount sufficient to reduce the symptoms of HD disease or condition. A therapeutically effective amount may vary depending on the subject and 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 one of ordinary skill in the art.

[0183] The methods described herein can be applied to in vivo or ex vivo cell populations. "In vivo" means within an individual organism, such as an animal or human. In this context, the methods described herein can be used therapeutically in an individual. "Ex vivo" means outside of an individual organism. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from an individual. Such samples can be obtained by methods well known in the art. Representative 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 optimal schedules and / or dosages of administration of the compounds of the invention for a given condition, cell type, individual, and other parameters. Information gathered from such uses can be used to design in vivo treatment protocols for experimental purposes or in the clinic. Other ex vivo uses for which the compounds and compositions described herein may be suitable are described below or will become apparent to those skilled in the art. Selected compounds can be further characterized to determine their safety or tolerability in human or non-human subjects. Such properties can be determined using methods commonly known to those skilled in the art.

[0184] In some embodiments, the compounds provided herein bind a target protein, mHTT, and an E3 ubiquitin ligase complex. It is contemplated that this ternary complex formation results in the transfer of multiple ubiquitin molecules to mHTT. Upon dissociation of the complex, polyubiquitinated mHTT is recognized and degraded by the proteasome.

[0185] Some embodiments provide a method of inducing degradation of mHTT, the method comprising administering a therapeutically effective amount of a compound described herein or a pharmaceutical composition described herein.

[0186] In some embodiments, degradation of mHTT provides a treatment for diseases caused by aggregation of mHTT.

[0187] The compounds disclosed herein are useful in the treatment of neurodegenerative diseases.

[0188] In some embodiments, the neurodegenerative disease is 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, the 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 of treating Huntington's disease, the method comprising administering a therapeutically effective amount of a compound described herein or a pharmaceutical composition described herein.

[0192] Combination therapy In some embodiments, the compounds disclosed herein can be used in combination with one or more additional therapeutic agents used and / or being developed to treat neurodegenerative diseases.

[0193] In some embodiments, the compounds disclosed herein can be used in combination with one or more additional therapeutic agents used and / or being developed to treat HD.

[0194] In some embodiments, the one or more additional therapeutic agents may be compounds that activate E3 enzymes that may otherwise be downregulated by mHTT.

[0195] In some embodiments, the one or more additional therapeutic agents can be inhibitors to enhance cellular uptake, such as p-glycoprotein 1 (pgp), or breast cancer resistance protein (BCRP) efflux inhibitors, such as elacridar.

[0196] kit Also provided herein are kits comprising a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, and suitable packaging. In some embodiments, the kit further comprises instructions for use. In some embodiments, the kit comprises a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, and a label and / or instructions for using the compound in treating a condition, including a disease or condition described herein.

[0197] Also provided herein is an article of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, in a suitable container, which may be a vial, bottle, ampoule, pre-filled syringe, or intravenous infusion bag.

[0198] Pharmaceutical Compositions and Modes of Administration The compounds provided herein are typically administered in the form of pharmaceutical compositions. Accordingly, pharmaceutical compositions containing one or more of the compounds described herein or their pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers, and 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 including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. Such compositions are prepared by methods well known in the pharmaceutical arts. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th Edition (1985), and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd Edition (eds. G.S. Banker and C.T. Rhodes).

[0199] The pharmaceutical compositions can be administered in either single or multiple doses. The pharmaceutical compositions can be administered by a variety of methods, including, for example, rectal, oral, intranasal, and transdermal routes. In certain embodiments, the pharmaceutical compositions can be administered by intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhalant.

[0200] One mode of administration is parenteral, for example, by injection. Forms into which the pharmaceutical compositions described herein can 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 with 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, via capsules or enteric-coated tablets. In preparing pharmaceutical compositions containing at least one compound described herein or its pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers, the active ingredient is usually diluted with an excipient and / or enclosed in a carrier, which may be in the form of a capsule, sachet, paper, or other container. When an excipient serves as a diluent, it 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, the composition may be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), ointment 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. Formulations can additionally include lubricating agents, such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives, such as methyl and propylhydroxybenzoates; sweetening agents; and flavoring agents.

[0203] Compositions containing at least one compound described herein or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof can be formulated to provide rapid, sustained, 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 set forth in U.S. Patent Nos. 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation for use in the methods disclosed herein employs transdermal delivery devices (patches). 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 is well known in the art. See, for example, US Patent Nos. 5,023,252, 4,992,445 and 5,001,139. ​​Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0204] To prepare solid compositions, such as tablets, the primary active ingredient can be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof. When these preformulation compositions are referred to as homogeneous, the active ingredient can be dispersed evenly throughout the composition so that the composition can be easily subdivided into equal, effective unit dosage forms, such as tablets, pills, and capsules.

[0205] Tablets or pills of the compounds described herein can be coated or otherwise formulated to provide a dosage form that offers the advantage of prolonged action or to protect against the acidic conditions of the stomach. For example, the tablet or pill can comprise an inner and outer component, the latter being in the form of an outer shell over the former. The two components can be separated by an enteric layer that helps resist disintegration in the stomach and allows the inner component to pass intact into the duodenum or be released later. A variety of materials can be used for such enteric layers or coatings, including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0206] Compositions for inhalation or insufflation 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 by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents can be nebulized by use of an inert gas. Nebulized solutions can be inhaled directly from the nebulizing device, or the nebulizing device can be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can 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 the present application for any particular subject will depend on various factors, including the activity of the specific compound employed, the age, weight, general health, sex, diet, time of administration, route of administration and excretion rate of the subject being treated, the drug combination, and the severity of the particular disease. For example, dosages can be expressed as milligrams of a compound described herein per kilogram of subject body weight (mg / kg). Dosages between about 0.1 and 150 mg / kg may be appropriate. In some embodiments, dosages between about 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 body weight is particularly useful when adjusting dosages between subjects of widely different sizes, for example, when using drugs in both pediatric and adult humans, or when converting effective dosages in non-human subjects, such as dogs, to dosages suitable for human subjects.

[0208] The daily dosage can also be described as the total amount of the compounds described herein administered per dose or per day. The daily dosage of the compounds described herein can be between about 1 mg and 4,000 mg, between about 2,000-4,000 mg / day, between about 1-2,000 mg / day, between about 1-1,000 mg / day, between about 10-500 mg / day, between about 20-500 mg / day, between about 50-300 mg / day, between about 75-200 mg / day, or between about 15-150 mg / day.

[0209] For oral administration, the total daily dosage for a human subject can be between 1 mg and 1,000 mg, between about 1,000-2,000 mg / day, between about 10-500 mg / day, between about 50-300 mg / day, between about 75-200 mg / day, or about 100-150 mg / day.

[0210] The compounds of the present application or compositions thereof can be administered once, twice, three times, or four times daily using any suitable regimen, as described above, and administration or treatment with the compounds can continue for several days, for example, generally, treatment can continue for at least 7, 14, or 28 days per treatment cycle.

[0211] Treatment cycles can be used, frequently alternating with rest periods of about 1 to 28 days, typically about 7 days or about 14 days, between cycles. Treatment cycles can be continuous in other embodiments.

[0212] Compound synthesis The compounds can be prepared using the methods disclosed herein, and routine modifications thereof that will be apparent given 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 exemplary compounds described herein can be achieved as described in the following examples. When available, reagents can be purchased from, for example, Sigma Aldrich or other chemical suppliers.

[0213] general synthesis Exemplary embodiments of the compounds described herein can be synthesized using the general reaction schemes set forth below. It will be apparent from the description herein that the general schemes can be modified by substituting other materials of similar structure to yield correspondingly different products. The syntheses that follow provide numerous examples of how starting materials can be varied to yield the corresponding products. Given a desired product with defined substituents, the necessary starting materials can generally be determined by inspection. Starting materials are typically obtained from commercial sources or synthesized using published methods. To synthesize a compound that is an embodiment described herein, inspection of the structure of the compound to be synthesized will provide the identity of each substituent. Given the examples herein, the identity of the final product will generally reveal the identity of the necessary starting materials through a simple workup process. In general, the compounds described herein are typically stable and isolatable at room temperature and pressure.

[0214] The compound of formula (I) can be synthesized by the following representative synthetic route.

[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, compound 1-1 and compound 1-2 are coupled under appropriate conditions (e.g., via a Mitsunobu reaction) to form compound 1-3. Suitable deprotection of compound 1-3 provides compound 1-4. Compounds of Formula (I) are prepared from coupling 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, compound 2-1 and compound 2-2 are coupled under appropriate conditions (e.g., in the presence of a base) to form compound 2-3. A compound of Formula (I) is prepared 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 are each independently L as described herein, and W, ULM, and B are as described herein. As shown in Scheme 3, in some embodiments, compounds of Formula (I)(i) can be prepared by coupling compounds 3-1 and 3-2 together using standard coupling conditions (e.g., the azide-substituted L of compound 3-1). A and 3-2 alkynyl-substituted L B This can be achieved by coupling (by click chemistry between [Example]

[0221] The following examples are included to represent specific embodiments of the invention. It should be understood by those skilled in the art that the techniques disclosed in the following examples represent techniques that may work well in the practice of the invention and thus can be considered to constitute specific modes of its practice. However, those skilled in the art should, in light of the present invention, understand that numerous changes in the specific embodiments disclosed can be made and still obtain like or similar results without departing from the spirit and scope of the invention.

[0222] General synthetic procedures: Commercially available reagents and solvents (HPLC grade) were used without further purification. 1 H NMR spectra were recorded on a Bruker DRX 500 MHz spectrometer or a Bruker DPX 250 MHz spectrometer in deuterated solvents. Chemical shifts (δ) are in parts per million. Thin layer chromatography (TLC) analysis was performed on Kieselgel 60 F 254 (Merck) plates 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 to 100% B over 3 min (A = water / 0.1% formic acid, B = acetonitrile / 0.1% formic acid), a 3 μL injection volume, 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 acquired over the m / z range of 150-850 using analytical HPLC-MS on a Shimadzu LCMS-2010EV system using a Waters LCT or reverse-phase Waters Atlantis dC18 column (3 μm, 2.1 × 100 mm), a gradient of 5-100% B over 7 min (A = water / 0.1% formic acid, B = acetonitrile / 0.1% formic acid), an injection volume of 3 μl, and a flow rate of 0.6 mL / min, at a sampling rate of 2 scans per second. 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 on a Bruker ASCEND 500 spectrometer. Spectra are reported in ppm (δ), and coupling constants, J values, are 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), a Waters Acquity SQD (ESI, UP-LCMS), or a 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 by UV absorbance at 254 nm.

[0225] [Table 3]

[0226] [Table 4]

[0227] Abbreviation AcOH - acetic acid aq - water-based Boc - tert-butyloxycarbonyl CMBP - Cyanomethyltributylphosphorane 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 EtOAc - 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 - phenyl ppm - parts per million rt- room temperature sat. - saturation TBME - tert-butyl methyl ether tBu - tert-butyl TFA - Trifluoroacetic acid THF - tetrahydrofuran TLC - Thin Layer Chromatography Ts - p-toluenesulfonyl UV - ultraviolet light

[0228] [Synthesis Example] [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 min and then treated dropwise with a solution of DIAD (192 μL, 0.98 mmol) in THF (2.5 mL) over 5 min. The mixture was stirred at 0 °C for an additional 10 min and then at room temperature overnight. The reaction mixture was concentrated to a low volume and then diluted with water (20 mL) and extracted with DCM (4 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO, filtered, and concentrated in vacuo. The crude material was purified by acidic reverse phase chromatography (C-18, 0-100% MeCN / water + 0.1% formic acid) to afford 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 4 N HCl in dioxane (4 mL) was stirred at room temperature for 3 hours. After this time, the reaction was evaporated to dryness to give 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-phenylbutanamido]-4-methylpentanamido]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-methyl-pentanoic acid (160 mg, 0.36 mmol), HOBT (124 mg, 0.81 mmol), and EDC.HCl (276 mg, 1.44 mmol) cooled to 0° C. The mixture was stirred at 0° C. for 15 min and allowed to warm to room temperature overnight. The reaction was concentrated to dryness, and the crude oil was partitioned between water and EtOAc. The aqueous layer was extracted once more, then the combined extracts were washed with 10% citric acid (aq), saturated NaHCO3 (aq), and brine. The organic layer was dried over MgSO4, filtered, and evaporated to dryness to give 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-phenylbutanamido]-4-methylpentanamido]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-phenylbutanamido]-4-methylpentanamido]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 h. The mixture was concentrated to a low volume and then acidified to pH 4 / 5 with 10% citric acid solution. The aqueous phase was extracted with DCM (4 × 15 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated to dryness to give 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-(pyridin-3-yl)-1,3-benzoxazol-5-yl]carbamoyl}pyridin-3-yl)oxy]ethoxy}ethoxy)ethoxy]ethyl}carbamoyl)butyl]carbamoyl}-3-phenylpropan-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-phenylbutanamido]-4-methylpentanamido]ethoxy}ethoxy)ethoxy]ethoxy}pyridine-2-carboxylic acid (110 mg, 0.16 mmol), and 2-(pyridin-3-yl)-1,3-benzoxazol-5-amine (33 mg, 0.16 mmol) in THF (2 mL) cooled to 0° C. After 1.5 h, the reaction was evaporated to dryness and then partitioned between EtOAc and 10% citric acid. The organic layer was washed with saturated NaHCO3(aq) (2x), dried over Na2SO4, filtered and evaporated to dryness to give 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-phenylbutanamido]-4-methylpentanamido]ethoxy}ethoxy)ethoxy]ethoxy}-N-[2-(pyridin-3-yl)-1,3-benzoxazol-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-(pyridin-3-yl)-1,3-benzoxazol-5-yl]carbamoyl}pyridin-3-yl)oxy]ethoxy}ethoxy)ethoxy]ethyl}carbamoyl)butyl]carbamoyl}-3-phenylpropan-2-yl]carbamate (138 mg, 0.15 mmol) in MeOH (1 mL). The reaction was stirred at room temperature for 1 h and then evaporated to dryness. The crude was dissolved in water and extracted with EtO. The aqueous layer was neutralized with solid NaHCO and then extracted with EtOAc (3 × 20 mL). The combined EtOAc extracts were washed with brine, dried over MgSO, filtered, and evaporated to dryness. The crude residue was purified by acidic reverse-phase chromatography (C-18, 0-100% MeCN / water + 0.1% formic acid) to give 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 TIFF2025032084000048.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-benzoxazol-5-yl]pyridine-2-carboxamide 6-(5-Amino-1,3-benzoxazol-2-yl)-2-methyl-pyridazin-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 was allowed to warm to room temperature overnight. Water was added slowly to induce precipitation. The resulting precipitate was isolated on filter paper and dried under vacuum to give 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-dihydropyridazin-3-yl)-1,3-benzoxazol-5-yl]carbamoyl}pyridin-3-yl)oxy]ethoxy}acetate 5-Hydroxy-N-[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazol-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 in one portion, and the suspension was stirred for 10 minutes. After this time, DIAD (230 μL, 1.16 mmol) was added, and the suspension was stirred overnight. The solid was isolated on a filter to give 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-dihydropyridazin-3-yl)-1,3-benzoxazol-5-yl]carbamoyl}pyridin-3-yl)oxy]ethoxy}acetic acid tert-Butyl 2-{2-[(6-{[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazol-5-yl]carbamoyl}pyridin-3-yl)oxy]ethoxy}acetate (150 mg, 0.29 mmol) was suspended in THF:water (5 mL:2 mL). KCO (80 mg, 0.58 mmol) was added and the reaction was stirred rapidly at room temperature overnight. No conversion to the desired product was observed. The reaction was concentrated, suspended in DCM (10 mL), TFA (2 mL) was added and the reaction was stirred overnight. The reaction was concentrated and then directly purified by acidic prep-HPLC to give 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-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methoxy)ethoxy]-N-[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazol-5-yl]pyridine-2-carboxamide (compound 51) (2R,4S)-1-[(2R)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (11 mg, 0.03 mmol) and 2-{2-[(6-{[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazol-5-yl]carbamoyl}pyridin-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 was stirred overnight and then directly purified by basic prep-HPLC to give 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-benzoxazol-5-yl]oxy}methyl)pyridin-3-yl]oxy}ethoxy)ethoxy]ethyl}carbamate To a solution of tert-butyl N-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}carbamate (57 mg, 0.229 mmol), 6-{5-[(5-hydroxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-2-methyl-2,3-dihydropyridazin-3-one (110 mg, 0.229 mmol), and Ph3P (90 mg, 0.344 mmol) in DMF (0.8 mL) was added DIAD (68 μL, 0.344 mmol). The resulting mixture was stirred at room temperature for 36 h, then evaporated to dryness, adsorbed onto silica, and purified by FCC (silica, 0-10% MeOH in DCM) to give 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}pyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-2-methyl-2,3-dihydropyridazin-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-dihydropyridazin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)pyridin-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 h and then partitioned between DCM and 2 N HCl (aq). The organic layer was extracted once more with 2 N HCl. The combined aqueous layers were neutralized with NaCO and then extracted with DCM (3×). The combined organic layers were dried over MgSO, filtered, and evaporated to dryness to give 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-benzoxazol-5-yl]oxy}methyl)pyridin-3-yl]oxy}ethoxy)ethoxy]ethyl}-2-(4-phenylbutanamido)pentanamide (compound 52) DIPEA (61 μL, 0.351 mmol) was added to a solution of 6-{5-[(5-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}pyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-2-methyl-2,3-dihydropyridazin-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 was stirred at room temperature while being monitored by LCMS. After 7 h, the reaction was partitioned between water and EtOAc. 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 give 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-benzoxazol-5-yl]oxy}methyl)pyridin-3-yl]oxy}ethoxy)ethoxy]ethyl}-2-(4-phenylbutanamido)pentanamide DIPEA (61 μL, 0.350 mmol) was added to a solution of 6-{5-[(5-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}pyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-2-methyl-2,3-dihydropyridazin-3-one (74%, 35 mg, 0.054 mmol), (2S)-2-[[(2S,3R)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenyl-butanoyl]amino]-4-methyl-pentanoic acid (23 mg, 0.054 mmol), EDC.HCl (41 mg, 0.215 mmol), and HOBT (19 mg, 0.121 mmol) cooled to 0° C. The solution was then allowed to warm to room temperature for 18 hours. After this time, the reaction mixture was partitioned between water and EtOAc. 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 give 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-phenylbutanamido]-4-methyl-N-{2-[2-(2-{[6-({[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)pyridin-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-dihydropyridazin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)pyridin-3-yl]oxy}ethoxy)ethoxy]ethyl}-2-(4-phenylbutanamido)pentanamide (12 mg, 0.014 mmol) in MeOH (0.15 mL) stirred at room temperature. After 3.5 h, the reaction was evaporated to dryness and the residue was partitioned between EtOAc and saturated NaHCO3(aq). The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered, and evaporated to dryness. The crude material was purified by acidic prep HPLC to give 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) and cooled to 0 °C, and sodium hydride (60% dispersion in mineral oil, 779 mg, 19.46 mmol) was added portionwise. The reaction was stirred at 0 °C for 5 min, then [2-(chloromethoxy)ethyl]trimethylsilane (2.76 mL, 15.57 mmol) was added over 5 min, and the resulting mixture was stirred at 0 °C for 1 h. 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 extractions were combined and evaporated to dryness to give a crude dark red oil, which was dissolved in a water:MeOH mixture (1:1, 30 mL) and treated with LiOH.HO (653 mg, 15.57 mmol). The reaction was stirred at room temperature for 1 hour, then concentrated to a low volume and acidified with a 10% solution of citric acid (aq) to pH 4. The aqueous phase was extracted with DCM and the combined extracts were washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give 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 in one portion, and the reaction was stirred overnight. Water was added to the reaction mixture, and the precipitated solid was filtered and washed with water. The crude residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (3 × 15 mL), and 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 give 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 at

[0257] Step 3: 6-(5-nitro-1,3-benzoxazol-2-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydropyridazin-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 was stirred at room temperature for 1.5 h. The reaction was diluted with DCM and washed with water and brine. The organic layer was dried over MgSO, filtered, and adsorbed onto silica. The crude material was purified by FCC (silica, 0-50% EtOAc in heptane) to give 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-dihydropyridazin-3-one TFA (1.00 mL, 13.06 mmol) was added dropwise to a solution of 6-(5-nitro-1,3-benzoxazol-2-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydropyridazin-3-one (100 mg, 0.257 mmol) in DCM (10 mL), and the mixture was stirred at room temperature overnight. The reaction was quenched with a saturated solution of NaHCO3(aq). The organic solvent was removed in vacuo, and the precipitated yellow solid was triturated in aqueous solution for 5 minutes and then collected by filtration. The solid was then dried under vacuum at 40°C for 5 hours to give 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-benzoxazol-2-yl)-6-oxo-1,6-dihydropyridazin-1-yl]ethoxy}ethoxy)ethyl]carbamate K2CO3 (33 mg, 0.241 mmol) was added in one portion 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-benzoxazol-2-yl)-2,3-dihydropyridazin-3-one (41 mg, 0.161 mmol) in DMF (1.5 mL). The reaction mixture was stirred at room temperature for 22 h and then partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated to dryness. The crude material was purified by FCC (silica, 0–5% MeOH in DCM) to give 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-benzoxazol-2-yl)-6-oxo-1,6-dihydropyridazin-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-benzoxazol-2-yl)-6-oxo-1,6-dihydropyridazin-1-yl]ethoxy}ethoxy)ethyl]carbamate (210 mg, 0.429 mmol) in EtOH (10 mL) and water (1 mL). The mixture was heated to reflux for 3 h, then cooled to room temperature and filtered through Celite. The filtrate was evaporated to dryness and the residue was diluted with EtOAc / water and extracted with EtOAc (3 x 15 mL). The combined organic layers were dried over MgSO4, filtered and evaporated to dryness to give 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-methoxypyridin-2-amido)-1,3-benzoxazol-2-yl]-6-oxo-1,6-dihydropyridazin-1-yl}ethoxy)ethoxy]ethyl}carbamate To a stirred solution of DIPEA (197 μL, 1.132 mmol), tert-butyl N-[2-(2-{2-[3-(5-amino-1,3-benzoxazol-2-yl)-6-oxo-1,6-dihydropyridazin-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 was added HATU (172 mg, 0.453 mmol). The mixture was stirred at room temperature for 6 h. The reaction was then extracted into EtOAc (15 mL) and washed successively with 10% citric acid (aq) solution, saturated NaHCO (aq) solution, and brine. The organic layer was dried over MgSO, filtered, and evaporated to dryness. The crude was purified by FCC (silica, 0-4% MeOH in DCM) to give 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-dihydropyridazin-3-yl)-1,3-benzoxazol-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-methoxypyridin-2-amido)-1,3-benzoxazol-2-yl]-6-oxo-1,6-dihydropyridazin-1-yl}ethoxy)ethoxy]ethyl}carbamate (65 mg, 0.109 mmol) in MeOH (0.5 mL) and stirred at room temperature for 4 hours. The reaction was then evaporated to dryness to give 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-methoxypyridin-2-amido)-1,3-benzoxazol-2-yl]-6-oxo-1,6-dihydropyridazin-1-yl}ethoxy)ethoxy]ethyl}carbamoyl)-3-methylbutyl]carbamoyl}-3-phenylpropan-2-yl]carbamate DIPEA (160 μL, 0.918 mmol) was added to a stirred suspension of N-[2-(1-{2-[2-(2-azaniumylethoxy)ethoxy]ethyl}-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazol-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-methyl-pentanoic acid (60 mg, 0.141 mmol), EDC.HCl (108 mg, 0.565 mmol) and HOBT (49 mg, 0.318 mmol) at 0 °C. The resulting mixture was stirred at 0°C and then warmed to room temperature over 2 hours. The reaction was partitioned between water and EtOAc. The organic layer was washed successively with 10% citric acid solution (aq), a saturated solution of NaHCO3 (aq), and brine. The organic phase was dried over MgSO4, filtered, and evaporated to dryness to give 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 min, (ES) + [M+H] + 885.

[0264] Step 10: N-(2-{1-[2-(2-{2-[(2S)-2-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutanamido]-4-methylpentanamido]ethoxy}ethoxy)ethyl]-6-oxo-1,6-dihydropyridazin-3-yl}-1,3-benzoxazol-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-methoxypyridin-2-amido)-1,3-benzoxazol-2-yl]-6-oxo-1,6-dihydropyridazin-1-yl}ethoxy)ethoxy]ethyl}carbamoyl)-3-methylbutyl]carbamoyl}-3-phenylpropan-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 was then evaporated to dryness and purified by chiral prep HPLC (methanol, Chiralcel OJ-H 25 cm column at 15 mL / min) to give 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 Example 6

[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), 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 min and then treated dropwise with DIAD (0.77 mL, 3.92 mmol). The mixture was stirred at 0 °C for an additional 30 min and then at room temperature overnight. The reaction mixture was then concentrated to dryness, and the crude material was dissolved in EtOAc (100 mL). The organic layer was washed with water (30 mL) and brine (30 mL), dried over NaSO, filtered, and evaporated under reduced pressure to give a brown oil that was purified by FCC (silica, 10–45% EtOAc in heptane) to give 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-methylthiazol-5-yl)phenol (400 mg, 0.563 mmol) in THF (3 mL) and MeOH (3 mL) was added 1 M NaOH (1.13 mL, 1.13 mmol), and the reaction was stirred at room temperature for 2.5 h. The reaction was neutralized with 1 M HCl (1.13 mL) at 0 °C, and then the solvent was removed in vacuo. MeCN (2.0 mL) was added, and then the crude product was purified by reverse-phase chromatography (C-18, 10-100% MeCN / water + 0.1% formic acid). Pure fractions were combined, and the solvent was removed in vacuo to give the title compound. Tr (METCR1410) = 0.96 min, (ES + ) [M+H] + 356.

[0269] Step 3: tert-Butyl 3-(2-{2-[(6-{[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazol-5-yl]carbamoyl}pyridin-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), HATU (224 mg, 0.59 mmol) in DMF (5 mL) at 0° C. under nitrogen was treated with the 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-benzoxazol-2-yl)-2-methyl-pyridazin-3-one (120 mg, 0.49 mmol). The resulting mixture was stirred at 0° C. for 1 hour and then at room temperature over the weekend. The reaction mixture was then concentrated in vacuo, 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 in a high vacuum oven at 40° C. overnight to give 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 min. (ES + ) [M+H] + 580.

[0270] Step 4: 3-(2-{2-[(6-{[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazol-5-yl]carbamoyl}pyridin-3-yl)oxy]ethoxy}ethoxy)propanoic acid A stirred solution of tert-butyl 3-(2-{2-[(6-{[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazol-5-yl]carbamoyl}pyridin-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 at room temperature overnight. The reaction mixture was then re-treated with TFA (0.28 mL, 3.6 mmol) and stirred at room temperature for an additional 24 h. The reaction mixture was then concentrated in vacuo, and the residue was diluted with water (10 mL) and neutralized with a saturated solution of NaHCO3(aq) at 0 °C. The precipitated solid was collected by filtration, washed with water, and then dried in a high vacuum oven at 40 °C for 4 h to provide 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-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}ethoxy)ethoxy]ethoxy}-N-[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazol-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-benzoxazol-5-yl]carbamoyl}pyridin-3-yl)oxy]ethoxy}ethoxy)propanoic acid (80 mg, 0.15 mmol), HATU (87 mg, 0.23 mmol) in DMF (2.5 mL) was stirred under nitrogen at 0° C. and treated with the 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-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (78 mg, 0.17 mmol). The resulting mixture was stirred at 0° C. for 1 hour and then at room temperature over the weekend. The reaction mixture was then directly purified by low-pH prep-HPLC. Pure fractions were combined, and the precipitated solid was collected by filtration and further dried in a vacuum oven at 50° C. for several hours to give 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] TIFF2025032084000055.tif218170TIFF2025032084000056.tif114170

[0274] [Example 7] Scheme for Example 7

[0275] [ka]

[0276] Step 1: 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate 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) and treated with finely crushed sodium hydroxide (0.23 g, 5.72 mmol), followed by the dropwise addition of a solution of 4-methylbenzenesulfonyl chloride (0.69 g, 3.62 mmol) in THF (20 mL) over 10 min. The resulting mixture was stirred at 0 °C for 3 h. The reaction mixture was then poured into an ice / water mixture (75 mL) and the mixture melted. 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), brine (2 × 50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude material was preabsorbed onto silica and purified by FCC (silica, 0–100% EtOAc in heptane). The clean fractions were combined, concentrated in vacuo and further dried under high vacuum to give 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 h. The reaction mixture was then cooled to room temperature, filtered through Celite, and the cake washed with acetone (10 mL). The filtrate was concentrated in vacuo, and the residue was dissolved in DCM (15 mL), washed with water (10 mL), brine (10 mL), dried over MgSO, filtered, concentrated in vacuo, and further dried under high vacuum to provide 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), 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 min and then treated dropwise with a solution of DIAD (100 μL, 0.51 mmol) in THF (5 mL) over 10 min. The mixture was stirred at 0 °C for an additional 43 min and then at room temperature overnight. The reaction was then concentrated to dryness to give the product, which was then purified by acidic reverse-phase chromatography (C-18, 10-100% MeCN / water with 0.1% formic acid) to give 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 in vacuo, and the remaining aqueous material was extracted with ether (3 × 5 mL). The aqueous phase was then acidified to pH 4 by the addition of a solution of 10% citric acid (1.5 mL). The mixture was extracted with EtOAc (3 × 15 mL). The combined organic extracts were washed with brine (15 mL), dried over MgSO4, filtered, concentrated in vacuo, and then further dried in a high vacuum oven at 50 °C to room temperature overnight to provide 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-oxo-pyridazin-3-yl)-1,3-benzoxazol-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]pyridin-3-yloxy)methylidene]-N-methylmethanaminium 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-benzoxazol-2-yl)-2-methyl-pyridazin-3-one (44 mg, 0.18 mmol). The mixture was stirred at 0 °C for 1 hour and then at room temperature overnight. The reaction mixture was then concentrated in vacuo and then 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 NaHCO (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 MgSO, filtered, and concentrated in vacuo. The crude material was purified by FCC (silica, 0–100% EtOAc in heptane followed by a flush of 10% MeOH in DCM) followed by acidic reverse-phase chromatography (C-18, 10–100% MeCN / water + 0.1% formic acid). The clean fractions were combined, concentrated in vacuo and further dried in a vacuum oven at 50° C. overnight to give 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-isoindol-2-yl)butanoyl]pyrrolidin-2-yl]formamido}methyl)-5-(4-methyl-1,3-thiazol-5-yl)phenoxy]ethoxy}ethoxy)ethoxy]ethoxy}-N-[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazol-5-yl]pyridine-2-carboxamide A sealed tube was charged with a solution of (4R)-4-hydroxy-N-[[2-hydroxy-4-(4-methylthiazol-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 KCO (19.21 mg, 0.14 mmol) was added. The suspension was stirred at room temperature for 10 minutes and then treated with a solution of 5-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]-N-[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,3-benzoxazol-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 and then allowed to reach room temperature. The reaction mixture was concentrated in vacuo, 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 organics were washed with brine (10 mL). The layers were separated, and the aqueous material was extracted with DCM (10 mL). The combined organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by acidic reverse-phase chromatography (C-18, 10-100% MeCN / water + 0.1% formic acid), and the clean fractions were triturated with ether and then repurified by acidic reverse-phase chromatography (C-18, 10-100% MeCN / water + 0.1% formic acid). The clean fractions were lyophilized overnight to give 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-oxo-pyridazin-3-yl)-1,3-benzoxazol-5-yl]oxymethyl]-3-pyridyl]oxy]ethoxy]ethoxy]acetate A stirred suspension of 6-[5-[(5-hydroxy-2-pyridyl)methoxy]-1,3-benzoxazol-2-yl]-2-methyl-pyridazin-3-one (160 mg, 0.46 mmol), 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 min and then treated dropwise with a solution of DIAD (134 μL, 0.69 mmol) in THF (5 mL) over 10 min. The mixture was stirred at 0 °C for an additional 16 min and then at room temperature overnight. The reaction mixture was then concentrated in vacuo, 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 and then treated dropwise with a solution of DIAD (134 μL, 0.69 mmol) in DMF (1 mL) over 2 minutes. The mixture was stirred at 0° C. for an additional 23 minutes and 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 min and then treated dropwise with a solution of DIAD (67 μL, 0.34 mmol) in DMF (1 mL) over 3 min. The mixture was stirred at 0° C. for an additional 15 min and then at room temperature overnight. The reaction mixture was then concentrated to dryness, and the crude material was purified by basic reverse-phase chromatography (C-18, 10-100% MeCN / HO+0.1% NHOH) to give 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-oxo-pyridazin-3-yl)-1,3-benzoxazol-5-yl]oxymethyl]-3-pyridyl]oxy]ethoxy]ethoxy]acetic acid A stirred solution of tert-butyl 2-[2-[2-[[6-[[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,3-benzoxazol-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 at room temperature overnight. The reaction mixture was then re-treated with TFA (0.15 mL, 1.96 mmol) and stirred at room temperature for an additional 6 h, after which the reaction mixture was concentrated in vacuo, azeotroped with DCM (2 × 10 mL), and further dried in a vacuum oven at 50 °C for several hours to give 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-benzoxazol-5-yl]oxy}methyl)pyridin-3-yl]oxy}ethoxy)ethoxy]acetamido}butanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide A stirred solution of 2-[2-[2-[[6-[[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,3-benzoxazol-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 min and then treated with (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (47 mg, 0.1 mmol). The mixture was stirred at 0° C. for 1 h and then at room temperature overnight. The reaction mixture was concentrated in vacuo, 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 NaHCO (aq) (10 mL) and brine (10 mL), dried over MgSO, filtered, and concentrated in vacuo. The crude material was purified by basic reverse-phase chromatography (C-18, 10-100% MeCN / water + 0.1% NHOH), followed by ether trituration (5 mL), to give 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), 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 min and then treated dropwise with DIAD (0.96 μL, 4.90 mmol) over 10 min. The mixture was stirred at 0 °C for an additional 30 min and then at room temperature overnight. The reaction mixture was then re-treated 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, and the reaction mixture was stirred for 20 min and then treated with DIAD (0.48 mL, 2.45 mmol). The mixture was stirred at 0 °C for an additional 30 min and then at room temperature for an additional 24 h. The reaction mixture was then concentrated to dryness, and the crude material was dissolved in EtOAc (50 mL). The organic layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure to give the crude product, which was purified by FCC (silica, 10-45% EtOAc in heptane, followed by 1-8% MeOH in DCM) to give 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)pyridin-3-yl]oxy}ethoxy)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) was added LiAlH (1.89 mL, 4.53 mmol) dropwise at −10° C. The reaction was allowed to warm to room temperature over 1 h. The reaction was cooled to 0° C. and then quenched with 1 M NaOH until no more gas was produced. A saturated solution of NaHCO (20 mL) was added. The resulting suspension was filtered through a pad of Celite, the solid was washed with EtOAc, and the combined organic layers were washed with brine, dried over NaSO, filtered, and evaporated under reduced pressure. The crude material was purified by FCC (silica, 10–45% EtOAc in heptane followed by 0–100% {10% MeOH in DCM} / DCM) to give 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]pyridin-3-yl}oxy)ethoxy]ethoxy}ethyl)carbamate tert-Butyl N-{2-[2-(2-{[6-(hydroxymethyl)pyridin-3-yl]oxy}ethoxy)ethoxy]ethyl}carbamate (350 mg, 0.66 mmol) was dissolved in DCM (8.0 mL), 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 h. Methanesulfonyl chloride (0.06 mL, 0.79 mmol) was added dropwise and the mixture was stirred at 0° C. for an additional 2 h. Water (20 mL) was carefully added to the cooled solution. The reaction mixture was allowed to warm to room temperature over 30 min, the phases were separated, and the aqueous phase was extracted with DCM (2×10 mL). The organic phases were combined, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound, which was 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-benzoxazol-5-yl]oxy}methyl)pyridin-3-yl]oxy}ethoxy)ethoxy]ethyl}carbamate 6-(5-Hydroxy-1,3-benzoxazol-2-yl)-2-methyl-2,3-dihydropyridazin-3-one (150 mg, 0.617 mmol) was dissolved in DMF (6.0 mL), then CsCO (508 mg, 1.54 mmol) was added in one portion. The reaction was stirred at room temperature for 1 h. A solution of tert-butyl N-(2-{2-[2-({6-[(methanesulfonyloxy)methyl]pyridin-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 h. The reaction mixture was stirred at 45 °C for an additional 18 h, then the solvent was removed in vacuo. The residue was suspended in water (50 mL). The product was extracted with EtOAc (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, 0-50% EtOAc in heptane, then 0-10% MeOH in DCM) followed by basic reverse-phase chromatography (C-18, 10-100% MeCN / water + 0.1% NH4OH) to give 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}pyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-2-methyl-2,3-dihydropyridazin-3-one tert-Butyl N-{2-[2-(2-{[6-({[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)pyridin-3-yl]oxy}ethoxy)ethoxy]ethyl}carbamate (185 mg, 0.318 mmol) was dissolved in DCM (5.0 mL), then TFA (0.06 mL, 0.79 mmol) was added dropwise at 0 °C. The reaction was stirred at room temperature for 2 h. The reaction mixture was quenched with a saturated solution of NaHCO3(aq) at 0 °C. The aqueous phase was extracted with DCM (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure to give an off-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 h. The solvent was removed in vacuo and the residue was dissolved in water (20 mL) and basified with a saturated solution of NaHCO3(aq). The aqueous phase was extracted with a solution of DCM:MeOH (5:1, 3 x 15 mL) and the combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure to give the title compound. Tr(METCR1410) = 0.88 min, (ES + ) (M+H) + 482.5.

[0298] Step 6: 2-(2,6-dioxopiperidin-3-yl)-4-({2-[2-(2-{[6-({[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)pyridin-3-yl]oxy}ethoxy)ethoxy]ethyl}amino)-2,3-dihydro-1H-isoindole-1,3-dione A sealed tube was charged with 6-{5-[(5-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}pyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-2-methyl-2,3-dihydropyridazin-3-one (50 mg, 0.104 mmol), 2-(2,6-dioxopiperidin-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 tube was flushed with nitrogen and placed on a preheated 90°C heating block for 4 hours. The reaction mixture was re-treated with 2-(2,6-dioxopiperidin-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 an additional 4 h. The reaction was cooled to room temperature, and the product was purified by low pH-prep. Pure fractions were combined and lyophilized overnight to give 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), 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 and then treated dropwise with DIAD (0.96 μL, 4.90 mmol) over 10 minutes. The mixture was stirred at 0° C. for an additional 30 minutes and then at room temperature overnight. Triphenylphosphine (428 mg, 1.63 mmol) was added, and the reaction mixture was stirred for 20 minutes and then treated dropwise with DIAD (0.32 mL, 1.63 mmol) over 10 minutes. The mixture was stirred at 0° C. for an additional 30 minutes and then at room temperature for an additional 6 hours. The reaction mixture was concentrated to dryness and the crude was suspended in water (50 mL). The aqueous material was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure to give a brown oil that was purified by FCC (silica, 10-45% EtOAc in heptane, followed by 1-8% MeOH in DCM) to give 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 To 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 added 1 M NaOH(aq) (1.37 ml, 1.37 mmol) at room temperature and the reaction was stirred for 3 h. The solvent was removed in vacuo and the aqueous phase was acidified with 1 M HCl and the pH adjusted to 2-3 at 0 °C. The aqueous phase was extracted with DCM (3 × 15 mL). The combined organic layers were dried over NaSO, filtered and evaporated under reduced pressure to give 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-benzoxazol-5-yl]carbamoyl}pyridin-3-yl)oxy]ethoxy}ethoxy)ethyl]carbamate A stirred solution of 5-{2-[2-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)ethoxy]ethoxy}pyridine-2-carboxylic acid (90 mg, 0.21 mmol), HATU (94 mg, 0.25 mmol) in DMF (2.5 mL) was stirred under nitrogen at 0° C. and treated with the dropwise addition of DIPEA (0.079 mL, 0.45 mmol). The reaction mixture was stirred at 0° C. for 15 min and then treated with 6-(5-amino-1,3-benzoxazol-2-yl)-2-methyl-2,3-dihydropyridazin-3-one (50 mg, 0.21 mmol). The resulting mixture was stirred at 0° C. for 1 h and then at room temperature for 4 h. The reaction mixture was then directly subjected to high-pH prep-HPLC in two portions. Pure fractions were combined and the solvent removed in vacuo. The resulting solid was dried in a high vacuum oven at 40° C. overnight to give 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-dihydropyridazin-3-yl)-1,3-benzoxazol-5-yl]pyridine-2-carboxamide tert-Butyl N-[2-(2-{2-[(6-{[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazol-5-yl]carbamoyl}pyridin-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 was stirred at room temperature for 3 hours and then left at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in water (15 mL) and basified 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 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 give 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-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]ethoxy}-N-[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazol-5-yl]pyridine-2-carboxamide A sealed tube was charged with 5-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}-N-[2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazol-5-yl]pyridine-2-carboxamide (70 mg, 0.14 mmol), 2-(2,6-dioxopiperidin-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 tube was flushed with nitrogen and placed on a preheated 90 °C heating block for 8 h. The reaction was cooled to room temperature, and the mixture was directly loaded onto low pH-prep HPLC in two portions. The pure fractions were combined and the solvent removed by lyophilization to give 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] TIFF2025032084000065.tif214170TIFF2025032084000066.tif81168

[0310] [Example 11] Scheme for Example 11

[0311] [ka]

[0312] Step 1: Ethyl 7-methoxybenzo[d]imidazo[2,1-b]thiazole-2-carboxylate. A mixture of 6-methoxybenzo[d]thiazol-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 h. After this time, another portion of ethyl 3-bromo-2-oxopropanoate (2.5 mL, 3.9 g, 20 mmol) was added, and heating was continued for an additional 24 h. The volatiles 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 h, 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 give two product fractions. The cleaner fraction was triturated with 95:5 heptane / ethyl acetate and filtered to give the product. The less clean fraction was dissolved in ethyl acetate (800 mL), and the solution was washed with 0.1 N HCl (3 × 100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the product. 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]thiazol-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 complete 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 layers were separated. The aqueous layer was extracted with ethyl acetate (3×35 mL), and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed (silica gel, ethyl acetate to 95:5 ethyl acetate / methanol, gradient elution) to give (7-methoxybenzo[d]imidazo[2,1-b]thiazol-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]thiazol-2-yl)pentaene-4-carbaldehyde (7-Methoxybenzo[d]imidazo[2,1-b]thiazol-2-yl)methanol (80 mg, 0.31 mmol) was dissolved in dichloromethane (5 mL) and treated with Dess-Martin periodinane (156 mg, 0.37 mmol). The mixture was stirred at room temperature for 64 h. The reaction was then quenched by the addition of saturated aqueous NaSO (2 mL) and saturated aqueous NaHCO (2 mL). The mixture was stirred for 5 min, causing 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 material was further extracted with dichloromethane (2 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried (MgSO), filtered, and concentrated to provide the title compound. 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]thiazol-2-yl)-3-(methyl-amino)imidazo-[1,2-a]pyridine-7-carbonitrile (7-Methoxybenzo[d]imidazo[2,1-b]thiazol-2-yl)pentaene-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 vacuum to give 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]thiazol-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]thiazol-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]thiazol-2-yl)methanol by methods 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 time, the crude product mixture was poured in portions into a vigorously stirred solution of saturated sodium bicarbonate (400 mL). Solid sodium bicarbonate was added periodically to maintain a pH of approximately 8. After the addition was complete, the crude product was collected by filtration as an orange solid. The filtrate was extracted with ethyl acetate (5 × 100 mL), and 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, and the mixture was concentrated to dryness, dried under high vacuum, and chromatographed (silica gel, dichloromethane to 91:9 dichloromethane / methanol, gradient elution) to give 2-(7-hydroxybenzo[d]imidazo[2,1-b]thiazol-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-Butyl 14-((2-(7-cyano-3-(methylamino)imidazo[1,2-a]pyridin-2-yl)benzo[d]imidazo[2,1-b]thiazol-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]thiazol-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 h. After this time, the mixture was cooled and concentrated under reduced pressure. The resulting residue was adsorbed onto silica gel and chromatographed (silica gel, ethyl acetate to 98:2 ethyl acetate / methanol, gradient elution). The product fractions were combined and rechromatographed (silica gel, dichloromethane to 96:4 dichloromethane / methanol, gradient elution) to give tert-butyl 14-((2-(7-cyano-3-(methylamino)imidazo[1,2-a]pyridin-2-yl)benzo[d]imidazo[2,1-b]thiazol-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]pyridin-2-yl)benzo[d]imidazo[2,1-b]thiazol-7-yl)oxy)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-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]pyridin-2-yl)benzo[d]imidazo[2,1-b]thiazol-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 h, TLC analysis indicated 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 an additional 2 h. After this time, the volatiles were removed under reduced pressure. The resulting residue was azeotroped with dichloromethane (2 × 20 mL), then toluene (2 × 20 mL) and again with dichloromethane (2 × 20 mL) to give crude 14-((2-(7-cyano-3-(methylamino)imidazo[1,2-a]pyridin-2-yl)benzo[d]imidazo[2,1-b]thiazol-7-yl)oxy)-3,6,9,12-tetraoxatetradecan-1oic acid.

[0319] Crude 14-((2-(7-cyano-3-(methylamino)imidazo[1,2-a]pyridin-2-yl)benzo-[d]imidazo[2,1-b]thiazol-7-yl)oxy)-3,6,9,12-tetraoxatetradecan-1oic acid (0.184 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methyl-thiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (0.0840 g, 0.195 mmol, Galdeano et al., J. Med. Chem. 2004) in N,N-dimethylformamide (8 mL). To a solution of 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 time, water (15 mL) was added, and 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 chromatographed (silica gel, dichloromethane to 92:8 dichloromethane / methanol, gradient elution) to afford the title compound. This material was dissolved in dichloromethane (3 mL) and precipitated by addition to heptane (25 mL). The resulting solid was collected by filtration and lyophilized from 50:50 acetonitrile / water (9 mL) to give the title compound. 1H NMR (500 MHz, DMSO-d6, observed as a 94:6 mixture of rotamers; chemical shifts of the major isomer are shown) 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] TIFF2025032084000069.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-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)-ethyl 4-methyl-benzenesulfonate A mixture of (2S,4R)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide (0.150 g, 0.273 mmol), ethane-1,2-diyl bis(4-methyl-benzenesulfonate) (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 time, the mixture was cooled to room temperature and filtered through a glass frit. The filter 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 chromatographed (silica gel, dichloromethane to 95:5 dichloromethane / methanol, gradient elution) to give 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]pyridin-2-yl)benzo[d]imidazo[2,1-b]thiazol-7-yl)oxy)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-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-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethyl 4-methylbenzenesulfonate (0.112 g, 0.150 mmol), 2-(7-hydroxybenzo[d]imidazo[2,1-b]thiazol-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. After this time, the mixture was cooled to room temperature, and ethyl acetate (15 mL), water (15 mL), and brine (15 mL) were added. The orange-brown precipitate that formed was removed by filtration, and the filtrate layers were separated. The aqueous layer was extracted with ethyl acetate (4 × 20 mL), and the organic layers were combined, washed with brine (4 × 20 mL), dried over sodium sulfate, and filtered. The solid collected before the 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 chromatographed (silica gel, dichloromethane to 93:7 dichloromethane / methanol, gradient elution) to give the title compound. The resulting 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 filter cake was washed with a mixture of heptane and ethyl acetate (95:5, 2 x 3 mL), dried under reduced pressure, lyophilized from 2:1 acetonitrile / water (10 mL), and dried in vacuo at 55°C for 2 hours to give the title compound. 1H NMR (500 MHz, DMSO-d6, mixture of rotamers, chemical shifts of the major rotamer are listed) 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 R = 6.41 minutes.

[0326] The following compounds were prepared as described above:

[0327] [Table 12] TIFF2025032084000072.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 time, the solvent was removed under reduced pressure, and the resulting residue was triturated with a 2:2:1 methylene chloride / ethyl acetate / methanol mixture (20 mL). The solid product was collected by filtration and rinsed with cold methanol (3 × 5 mL) to give 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-methylpyridazin-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 under microwave irradiation at 200° C. for 3.5 hours. After this time, the solvent was removed under reduced pressure and the resulting residue was triturated with a 2:2:1 methylene chloride / ethyl acetate / methanol mixture (10 mL) to provide 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-methyl-pyridazin-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]oxazol-2-yl)-2-methylpyridazin-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 and then heated at 80° C. for 2 hours. After this time, the reaction mixture was cooled to room temperature and quenched with water (100 mL). The product was extracted with methylene chloride (2×100 mL), and 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 give 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-hydroxypyridin-2-yl)methoxy)benzo[d]oxazol-2-yl)-2-methylpyridazin-3(2H)-one A mixture of 6-(5-((5-(allyloxy)pyridin-2-yl)methoxy)benzo[d]oxazol-2-yl)-2-methyl-pyridazin-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, and the mixture was purged with nitrogen for an additional 5 minutes, then heated at 50° C. for 2 hours. After this time, the solid product was collected by filtration, rinsed with methanol, adsorbed onto silica gel, and purified by chromatography (silica gel, methylene chloride to 90:10 methylene chloride / methanol, gradient elution) to give 6-(5-((5-hydroxypyridin-2-yl)methoxy)benzo[d]oxazol-2-yl)-2-methylpyridazin-3(2H)-one. The isolated product was recrystallized from DMSO and lyophilized to give 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)butan-oyl)-N-(2-(2-((6-(((2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzo[d]oxazol-5-yl)oxy)methyl)pyridin-3-yl)oxy)ethoxy)-4-(4-methylthiazol-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-carboxamido)-methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethyl 4-methylbenzenesulfonate (0.099 g, 0.13 mmol) and 6-(5-((5-hydroxypyridin-2-yl)methoxy)benzo[d]oxazol-2-yl)-2-methyl-pyridazin-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 h. After this time, the reaction mixture was 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 afford (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-dihydropyridazin-3-yl)benzo[d]oxazol-5-yl)oxy)methyl)pyridin-3-yl)oxy)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. This material was combined with another lot and purified by column chromatography (silica gel, dichloromethane to 86:14 dichloromethane / methanol, gradient elution). The resulting product was dissolved in a solution of 96:4 dichloromethane / methanol (1 mL) and added to a stirred solution of 88:12 heptane / ethyl acetate (13 mL). The suspension was stirred for 5 minutes, allowed to stand for 20 minutes, and filtered. The filter cake was washed with 88:12 heptane / ethyl acetate (2 x 5 mL), then dissolved in a solution of 1:1 acetonitrile / water (17 mL) and lyophilized to give the title compound. 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)pyridin-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)pyridin-3-ol (1.00 g, 7.99 mmol) and allyl bromide (0.80 mL, 9.3 mmol) in anhydrous acetone (10 mL), and the reaction mixture was heated at 60° C. for 2 hours in a sealed tube. After this time, 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 give 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 to a solution of (5-(allyloxy)pyridin-2-yl)methanol (1.45 g, 8.78 mmol) in anhydrous methylene chloride (30 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 minutes and at room temperature for 2 hours. After this time, the mixture was 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 provide 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)pyridin-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]-oxazol-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 time, 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, allowed to stand for 30 minutes, and filtered. The filter cake was washed with water (2×20 mL) and dried under vacuum to give the title compound. The filtrate from above was extracted with ethyl acetate (4 x 100 mL), and the combined organic layers were washed with water (2 x 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 give 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)pyridin-2-yl)methoxy)-2-aminophenol 2 M Hydrochloric acid (5.5 mL, 11 mmol) was added to a stirred solution of 5-((5-(allyl-oxy)pyridin-2-yl)methoxy)-2-methylbenzo[d]oxazole (0.538 g, 1.82 mmol) in ethanol (11 mL) at room temperature, and the resulting suspension was placed in a preheated aluminum block and stirred at 105° C. for 6 hours. After this time, the reaction mixture was 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 provide 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)pyridin-2-yl)methoxy)-2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)benzo[d]oxazole Dichlorodiphenoxymethane (0.3 g, 1.0 mmol) was added to a solution of 4-((5-(allyloxy)-pyridin-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), and the resulting reaction mixture was heated at 80 °C for 24 h. After this time, the mixture was slowly cooled to room temperature, diluted with dichloromethane (15 mL), and quenched with saturated sodium bicarbonate (15 mL). The mixture was stirred vigorously for 5 min, the phases were separated, and the aqueous phase was extracted with dichloromethane (3 × 20 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, dichloromethane to 90:10 dichloromethane / methanol, gradient elution) to the title compound. 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, 1.5 Hz, 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). 5-((5-(allyloxy)pyridin-2-yl)methoxy)-2-phenoxybenzo[d]oxazole was also isolated from the 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)pyridin-2-yl)methoxy)-2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)benzo[d]oxazole Cesium carbonate (0.305 g, 0.935 mmol) was added to a solution of 5-((5-(allyloxy)-pyridin-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 this time, the mixture was cooled to room temperature, quenched with water (30 mL), and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine (3×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, dichloromethane to 90:10 dichloromethane / methanol, gradient elution) to give 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, 1.5 Hz, 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]pyrazin-7(8H)-yl)benzo[d]oxazol-5-yl)oxy)methyl)pyridin-3-ol A mixture of 5-((5-(allyloxy)pyridin-2-yl)methoxy)-2-(5,6-dihydroimidazo[1,2-a]pyrazin-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 this time, the mixture was cooled to room temperature, diluted with water (100 mL), and extracted with dichloromethane (3 × 100 mL). The combined organic phases were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, dichloromethane to 90:10 dichloromethane / methanol, gradient elution) to give 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]pyrazin-7(8H)-yl)benzo-[d]oxazol-5-yl)oxy)methyl)pyridin-3-yl)oxy)ethoxy)ethoxy)ethoxy)acetic acid Sodium hydride (60% dispersion in mineral oil, 0.040 g, 1.1 mmol) was added to a solution of 6-(((2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)benzo[d]oxazol-5-yl)oxy)-methyl)pyridin-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) at 0° C. After 10 min, the mixture was heated at 50° C. for 4.5 h. After this time, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (2×50 mL). The aqueous phase was concentrated in vacuo and the resulting residue was adsorbed onto diatomaceous earth and purified by reverse phase chromatography (C18, 95:5 water / acetonitrile to acetonitrile, gradient elution) to give 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]pyrazin-7(8H)-yl)benzo[d]oxazol-5-yl)oxy)methyl)pyridin-3-yl)oxy)-4-oxo-6,9,12-trioxa-3-azatetra-decan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-pyrrolidine-2-carboxamide HATU (0.058 g, 0.15 mmol) was dissolved in 2-(2-(2-(2-((6-(((2-(5,6-dihydro-imidazo[1,2-a]pyrazin-7(8H)-yl)benzo[d]oxazol-5-yl)oxy)methyl)pyridin-3-yl)oxy)ethoxy)-ethoxy)ethoxy)acetic acid (0.085 g, 0.15 mmol) in N,N-dimethylformamide. To a solution of (2S,4R)-1-((S)-2-amino-3,3-dimethyl-butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (0.060 g, 0.14 mmol) and N,N-diisopropylethylamine (0.146 mL, 0.836 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After this time, saturated sodium carbonate (20 mL) was added, and the mixture was extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed with brine (3 × 30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, dichloromethane to 90:10 dichloromethane / / 9:1 methanol / ammonium hydroxide, gradient elution), and the resulting product was lyophilized from 1:1 water / acetonitrile to give 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)pyridin-2-yl)methoxy)benzo[d]oxazol-2-yl)piperazine-1-carboxylate Tetramethoxymethane (0.42 mL, 3.2 mmol) was added to a solution of 4-((5-(allyloxy)-pyridin-2-yl)methoxy)-2-aminophenol (0.426 g, 1.56 mmol), tert-butyl piperazine-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 time, 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 give 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-hydroxypyridin-2-yl)methoxy)benzo[d]oxazol-2-yl)piperazine-1-carboxylate A mixture of tert-butyl 4-(5-((5-(allyloxy)pyridin-2-yl)methoxy)benzo[d]oxazol-2-yl)piperazine-1-carboxylate (0.347 g, 0.744 mmol) and 1,3-dimethylbarbituric 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 at room temperature for 6 hours under argon. After this time, 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 to 95:5 dichloromethane / methanol, gradient elution) to give 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-Butyl 4-(5-((5-((3-oxo-2,5,8,11-tetraoxatridecan-13-yl)oxy)-pyridin-2-yl)methoxy)benzo[d]oxazol-2-yl)piperazine-1-carboxylate A solution of tert-butyl 4-(5-((5-hydroxypyridin-2-yl)methoxy)benzo[d]oxazol-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. After this time, the reaction mixture was 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 provide 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)piperazin-1-yl)benzo[d]-oxazol-5-yl)oxy)methyl)pyridin-3yl)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-tetraoxatridecan-13-yl)oxy)pyridin-2-yl)methoxy)benzo[d]oxazol-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 time, 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 provide 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-butyl 4-(5-((5-(((S)-13-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecyl)oxy)pyridin-2-yl)methoxy)benzo[d]oxazol-2-yl)piperazine-1-carboxylate HATU (0.090 g, 0.24 mmol) was dissolved in 2-(2-(2-(2-((6-(((2-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzo[d]oxazol-5-yl)oxy)methyl)pyridin-3-yl)oxy)ethoxy)-ethoxy)ethoxy)acetic acid (0.145 g, 0.235 mmol) in N,N-dimethylformamide (6.5 mL). To a suspension of (2S,4R)-1-((S)-2-amino-3,3-dimethyl-butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-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. After this time, the reaction mixture was diluted with saturated aqueous sodium carbonate (60 mL) and brine (20 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were 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 provide the title compound. 1H NMR (500 MHz, DMSO-d6, mixture of rotamers, chemical shifts of the major rotamer 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]oxazol-5-yl)oxy)methyl)pyridin-3-yl)oxy)-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide Trifluoroacetic acid (4.0 mL, 52 mmol) was added to a solution of tert-butyl 4-(5-((5-(((S)-13-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecyl)oxy)pyridin-2-yl)methoxy)benzo[d]oxazol-2-yl)piperazine-1-carboxylate (0.113 g, 0.110 mmol) in dichloromethane (4.0 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hour and at room temperature for 1 hour. After this time, 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 x 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 additive, loaded in 1:1 tetrahydrofuran / water, gradient elution). The product fraction was lyophilized to give the title compound. 1H NMR (500 MHz, DMSO-d6, mixture of rotamers, chemical shifts of the major rotamer 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), 7.25 (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-methoxypyridin-2-yl)methoxy)benzo[d]oxazol-2-yl)piperazine-1-carboxylate To a solution of 2-amino-4-((5-methoxypyridin-2-yl)methoxy)phenol (0.466 g, 1.89 mmol) in chloroform (15 mL) was added tert-butyl piperazine-1-carboxylate (0.705 g, 3.78 mmol), acetic acid (0.433 mL, 7.57 mmol), and tetramethoxymethane (0.504 mL, 3.78 mmol), and the mixture was heated at 60° C. overnight. After this time, the reaction mixture was 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 give 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-methoxypyridin-2-yl)methoxy)-2-(piperazin-1-yl)benzo[d]-oxazole To a solution of tert-butyl 4-(5-((5-methoxypyridin-2-yl)methoxy)benzo[d]oxazol-2-yl)piperazine-1-carboxylate (0.060 g, 0.14 mmol) in 1,4-dioxane (4 mL) was added 4 M hydrogen chloride in 1,4-dioxane (0.25 mL, 1.0 mmol), and the mixture was stirred at room temperature overnight. After this time, the reaction mixture was 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 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to provide 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-methoxypyridin-2-yl)methoxy)benzo-[d]oxazol-2-yl)piperazin-1-yl)ethoxy)ethoxy)ethoxy)acetate N,N-Diisopropylethylamine (0.21 mL, 1.2 mmol) was added to a solution of 5-((5-methoxypyridin-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 at reflux for 18 hours. After this time, 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 provide 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-methoxypyridin-2-yl)methoxy)benzo[d]oxazol-2-yl)piperazin-1-yl)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-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-methoxypyridin-2-yl)methoxy)benzo[d]oxazol-2-yl)piperazin-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 time, the reaction mixture was concentrated to dryness and solvent exchanged with dichloromethane (2 x 25 mL) to provide crude 2-(2-(2-(2-(4-(5-((5-methoxypyridin-2-yl)methoxy)benzo[d]oxazol-2-yl)piperazin-1-yl)ethoxy)ethoxy)ethoxy)acetic acid, trifluoroacetate salt. MS (DUIS) m / z 531 [M + H] + .

[0366] The crude 2-(2-(2-(2-(4-(5-((5-methoxypyridin-2-yl)methoxy)benzo[d]oxazol-2-yl)piperazin-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-methylthiazol-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), and the mixture was stirred at room temperature for 30 minutes. After this time, the reaction mixture was diluted with 1:1 water / saturated aqueous sodium bicarbonate (80 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were 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 fractions were concentrated under reduced pressure and lyophilized with 2:1 acetonitrile / water (7 mL) to give the title compound. 1H NMR (500 MHz, MeOD; mixture of rotamers, chemical shifts of the major rotamer are listed) 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-nitropyridin-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 h. The mixture was partitioned between water and EtOAc and extracted three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated to dryness. The crude material was adsorbed onto silica and purified by FCC (silica, 20 to 100% EtOAc in heptane) to give 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-aminopyridin-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-nitropyridin-2-yl)oxy]ethoxy}ethoxy)ethyl]carbamate (200 mg, 0.54 mmol) in EtOH (10 mL) and water (1 mL). The mixture was heated to reflux for 90 min, then cooled to room temperature and filtered through Celite. The filtrate was evaporated to dryness and partitioned between water and EtOAc. The aqueous layer was extracted once more with EtOAc. The combined layers were washed with brine, dried over MgSO4, filtered, and evaporated to dryness to give 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-hexaen-11-amido}pyridin-2-yl)oxy]ethoxy}ethoxy)ethyl]carbamate 1,8,10-Triazatricyclo[7.4.0.0 2,7]Trideca-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-aminopyridin-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 N for 3 hours, then diluted with water (5 mL). A dark yellow solid precipitated from the mixture, triturated for 5 minutes, collected by filtration, and washed with water. The solid was dried overnight in a vacuum oven at 40° C. to give 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}pyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7]Trideca-2,4,6,8,10,12-hexaene-11-carboxamide TFA (1 mL) was added to tert-butyl N-[2-(2-{2-[(5-{1,8,10-triazatricyclo[7.4.0.0 2,7 To a solution of ]trideca-2,4,6,8,10,12-hexaen-11-amido}pyridin-2-yl)oxy]ethoxy}ethoxy)ethyl]carbamate (200 mg, 0.373 mmol) was added dropwise. The mixture was allowed to warm to room temperature over 2 hours and 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 give 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 2,7]trideca-2,4,6,8,10,12-hexaen-11-amido}pyridin-2-yl)oxy]ethoxy}ethoxy)ethyl]carbamoyl}butyl]carbamoyl}-3-phenylpropan-2-yl]carbamate N-(6-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}pyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0] in DMF (1 mL) 2,7 To a mixture of 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-methyl-pentanoic acid (36 mg, 0.081 mmol), HOBT (28 mg, 0.182 mmol), and DIPEA (63 μL, 0.364 mmol) was added EDC.HCl (62 mg, 0.323 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 h. The mixture was partitioned between water (10 mL) and EtOAc (10 mL). The phases were separated, and the aqueous layer was extracted with additional EtOAc (3 × 10 mL). The combined organic layers were washed with 10% citric acid (aq) (10 mL), saturated NaHCO3 (aq) (2 × 10 mL), brine (1 × 10 mL), dried over MgSO4, filtered, and evaporated to dryness. The crude was purified by FCC (silica, 0-6% MeOH in DCM) to give 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-phenylbutanamido]-4-methylpentanamido]ethoxy}ethoxy)ethoxy]pyridin-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 [[(2,4,6,8,10,12-hexaen-11-amido}pyridin-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 and then stirred at room temperature for 4 hours. The reaction was diluted with MeOH and then evaporated to dryness. The crude was partitioned between saturated NaHCO3 (25 mL) and DCM (25 mL). The phases were separated and the aqueous layer was extracted with additional DCM (4 x 15 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated to dryness. The crude was adsorbed onto silica and purified by FCC (silica, 0-20% MeOH in DCM). The combined fractions were evaporated to dryness to give 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-nitropyridin-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 at reflux in a sealed tube for 4 h, then cooled to room temperature and partitioned between EtOAc 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 material was adsorbed onto silica and purified by FCC (silica, 25-100% EtOAc in heptane) to give 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-aminopyridin-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-nitropyridin-2-yl)amino]ethoxy}ethoxy)ethyl]carbamate (291 mg, 0.54 mmol) in EtOH (10 mL) and water (1 mL). The mixture was heated to reflux for 2 h. Additional NH4Cl (100 mg) and iron powder (50 mg) were added, and the reaction was stirred at reflux for 1 h. The reaction was cooled to room temperature and filtered through Celite, washing with EtOH. The filtrate was evaporated to dryness and then purified by FCC (silica, 0-20% MeOH in DCM) to give 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-amido}pyridin-2-yl)amino]ethoxy}ethoxy)ethyl]carbamate 1,8,10-Triazatricyclo[7.4.0.0 2,7]trideca-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 was stirred for 5 minutes. A solution of tert-butyl N-[2-(2-{2-[(5-aminopyridin-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 for 10 minutes at room temperature, filtered, and washed with additional water. The solid was dried in a vacuum oven overnight at 40 °C to give the title compound. 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-hexaen-11-amido}pyridin-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-amido}pyridin-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 was evaporated to dryness to give 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-amido}pyridin-2-yl)amino]ethoxy}ethoxy)ethyl]carbamoyl}butyl]carbamoyl}-3-phenylpropan-2-yl]carbamate 2-(2-{2-[(5-{1,8,10-triazatricyclo[7.4.0.0 2,7To a mixture of ]trideca-2,4,6,8,10,12-hexaen-11-amido}pyridin-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-methyl-pentanoic acid (94 mg, 0.21 mmol), HOBT (73 mg, 0.48 mmol), and DIPEA (240 μL, 1.38 mmol), EDC.HCl (162 mg, 0.85 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 7 hours. The reaction was partitioned between water (50 mL) and EtOAc (50 mL). The phases were separated and the aqueous layer was extracted with additional EtOAc (2 x 15 mL). The combined organic layers were washed with 10% citric acid (1 x 30 mL), saturated NaHCO (2 x 30 mL), and brine (30 mL). The organic layer was dried over NaSO, filtered, and evaporated to dryness. The crude was purified by FCC (silica, 0-10% MeOH in DCM) to give 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-phenylbutanamido]-4-methylpentanamido]ethoxy}ethoxy)ethyl]amino}pyridin-3-yl)-1,8,10-triazatricyclo[7.4.0.0 2,7 ]Trideca-2,4,6,8,10,12-hexaene-11-carboxamidoformate 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 [(2,4,6,8,10,12-hexaen-11-amido)(pyridin-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 in vacuo and partitioned between DCM (25 mL) and saturated NaHCO3 (50 mL). The aqueous layer was extracted with DCM (4 × 25 mL), and the combined extracts were washed with brine, dried over MgSO4, filtered, and evaporated to dryness. The crude material was purified by FCC (silica, 0-15% MeOH in DCM) and acidic reverse-phase chromatography (C-18, 0-100% MeCN / water + 0.1% formic acid) to give 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]pyridin-2-yl]imidazo[2,1-b][1,3]benzothiazol-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]benzothiazol-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 was stirred at 100° C. for 2 hours. The reaction was then cooled to room temperature, and the formed precipitate was filtered and washed with toluene to give the title compound. 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]benzothiazol-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 tert-butyl N-[2-[2-[2-[7-cyano-3-(methylamino)imidazo[1,2-a]pyridin-2-yl]imidazo[2,1-b][1,3]benzothiazol-6-yl]oxyethoxy]ethyl]carbamate (198 mg, 0.333 mmol) in 1,4-dioxane (5 mL) and MeOH (2.5 mL). The mixture was stirred at room temperature for 24 hours, after which additional 4N HCl in dioxane (0.20 ml) was added and the mixture was stirred at room temperature for a further 24 hours. The reaction was evaporated to dryness to give 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-isoindolin-4-yl]amino]ethoxy]ethoxy]imidazo[2,1-b][1,3]benzothiazol-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-fluoro-isoindoline-1,3-dione (57 mg, 0.207 mmol) and 2-[6-[2-(2-aminoethoxy)ethoxy]imidazo[2,1-b][1,3]benzothiazol-2-yl]-3-(methylamino)imidazo[1,2-a]pyridine-7-carbonitrile; hydrochloride (100 mg, 0.207 mmol) in DMF (2.5 mL). The solution was heated at 90° C. for 48 hours. The reaction was evaporated to dryness and purified by low pH prep HPLC to give 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]ethyl methanesulfonate A stirred solution of tert-butyl N-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}carbamate (250 mg, 1.00 mmol) and NEt (181 μL, 1.3 mmol) in DCM (5 mL) at 0° C. was treated with the dropwise addition of MsCl (93 μL, 1.2 mmol). After the addition, the mixture was stirred at 0° C. for 1.5 h and then at room temperature for 3 h. The reaction mixture was diluted with DCM (10 mL) and washed with a solution of saturated NaHCO (15 mL) and brine (15 mL). The organic layer was dried over MgSO, filtered, concentrated in vacuo, and further dried on a high vacuum line for 2 h to provide 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) was added KI (675 mg, 4.06 mmol). The resulting suspension was stirred at 50° C. overnight. 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 at 50° C. overnight. The reaction mixture was then treated with KI (300 mg, 1.81 mmol), and heating was continued for 3 h. The reaction mixture was then cooled to room temperature and partitioned between water (10 mL) and EtOAc (10 mL). The layers were separated, and the aqueous phase was extracted with EtOAc (4×15 mL). The combined organic phase was washed with a solution of saturated NaSO(aq) (20 mL) and brine (20 mL), dried over MgSO, filtered, and concentrated in vacuo to give the crude product. The crude product was pre-absorbed onto silica and purified by FCC (silica, 0-100% EtOAc in heptane). The pure fractions were combined, concentrated in vacuo, and further dried on a high vacuum line for 2 h to give 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 A sealed tube was charged with methyl 2-chloropyrimidine-4-carboxylate (250 mg, 1.45 mmol) 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, placed on a preheated heating block set at 100° C., and stirred for 1 hour, then at room temperature overnight. The reaction mixture was heated at 100° C. for an additional 5 hours and then allowed to stand at room temperature over the weekend. The reaction mixture was heated for an additional 6 hours and then allowed to reach room temperature. The red solution was then diluted with a solution of saturated NaHCO (8 mL), and the resulting mixture was extracted with EtOAc (4×15 mL). The combined organics were washed with brine (15 mL), dried over MgSO, filtered, and concentrated in vacuo to give the crude product. The crude material was pre-absorbed onto silica and purified by FCC (0-100% EtOAc in heptane) to give 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 charged 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 in one portion, and the mixture was stirred for 15 min. 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 min, and the mixture was further stirred at 0 °C for 10 min, room temperature for 1.5 h, 50 °C for 4 h, and 80 °C overnight. The reaction mixture was then cooled to room temperature and concentrated in vacuo to give the product. The product was suspended in THF (2 mL) and treated with 1 M LiOH (1 mL). The mixture was sonicated briefly and stirred at room temperature for 2.5 h. The reaction mixture was then concentrated in vacuo and the remaining aqueous material was extracted with ether (3 x 5 mL). The aqueous phase was then acidified to pH 4 by the addition of a solution of 10% citric acid (aq) (2 mL). The mixture was extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine (15 mL), dried over MgSO, filtered, concentrated in vacuo, and further dried in a vacuum oven to give the crude product. The crude residue was purified by acidic reverse-phase Biotage (C-18, 0-100% MeCN / water + 0.1% formic acid) to give 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]pyrimidin-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), N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (58 mg, 0.15 mmol) in DMF (2 mL) was stirred under nitrogen at 0° C. and treated with the 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 min and then treated with a solution of 6-methoxypyridin-3-amine (15.79 mg, 0.13 mmol) in DMF (1 mL). The resulting mixture was stirred at 0°C for 2 hours and then at room temperature overnight. The reaction mixture was then concentrated in vacuo, 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 x 10 mL). The combined organics were 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 in vacuo to give the crude residue. The crude residue was preabsorbed onto silica and purified by FCC (silica, 0-100% EtOAc in heptane) to give 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]pyrimidin-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 h. The reaction mixture was then concentrated in vacuo and further dried in a vacuum oven at 50° C. to give the title compound, obtained as a 1:1 mixture of the title compound and the O-demethylated 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-methyl-pentanoic acid (51 mg, 0.12 mmol) and 1H-benzotriazol-1-ol hydrate (1:1) (42 mg, 0.27 mmol) in DMF (2 mL) was sonicated briefly, then cooled on ice and treated with DIPEA (65 μL, 0.37 mmol) followed by EDC HCl (49 mg, 0.26 mmol). The mixture was stirred at 0° C. for 12 minutes and then at room temperature over the weekend. The reaction mixture was then concentrated in vacuo, and the resulting oily residue was partitioned between EtOAc (10 mL) and water (5 mL). The layers were separated, and the aqueous phase was extracted with EtOAc (3×10 mL). The combined organic extracts were washed successively with a solution of 10% citric acid (aq) (10 mL), a saturated solution of NaHCO3 (aq) (10 mL), brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo to give the product. 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 an additional 1.5 hours. The reaction mixture was then concentrated in vacuo, and the residue was dissolved in water (5 mL), treated with solid NaHCO3 (720 mg), and extracted with DCM (3 x 15 mL). The combined organic extracts were washed with brine (15 mL), dried over MgSO4, filtered, and concentrated in vacuo to give 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 in vacuo, and lyophilized overnight to give 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 could effectively displace radioligands from preformed polyQ46 or Exon1-polyQ46 (Q46_RBA) aggregates, as detailed elsewhere (see, e.g., U.S. Patent Application Publication No. 2017 / 0292150).

[0404] Aggregation of polyQ peptides is initiated by cleavage of the tag from the GST-polyQ46 or MBP-Exon1-polyQ46 fusion protein. The preformed aggregates are then analyzed for binding to the aggregates. 3 [H] Radiolabeled ligand is incubated with a competing compound. The readout is a MicroBeta measurement based on the scintillation of radioactive ligand bound to the aggregates. Activity is indicated as follows: +++ = <100 nM, ++ = 100-500 nM, and + = >500 nM.

[0405] [Table 19] TIFF2025032084000088.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 for their respective recombinant ligase complexes / domains.

[0407] The assay is based on surface plasmon resonance (SPR), which can measure changes in the local refractive index due to changes in molecular mass on the gold chip surface and in the flow system when a binding event occurs. To detect binding between both partners, each E3 ligase is immobilized on the chip surface, while the test compound is flowed over the chip surface at a constant rate. The detected change in RU response indicates a binding event and is concentration-dependent.

[0408] For SPR experiments, we used either a commercially available VHL complex (Merck, 23-044, consisting of 5 units: VHL, elongin B, elongin C, Cul2, and Rbx1) displaying a His-tag on the Cul2 subunit, or an in-house produced biotin-labeled mouse CRBN thalidomide-binding domain (mCRBN-TBD). These tags provide an anchor for the capture process onto either NTA- or streptavidin-coated chip surfaces (immobilization levels of 3,000–5,000 RU). Because the VHL complex has a somewhat complex structure, further binding to the chip surface by amino coupling prevents any protein loss due to complex collapse during flow systems.

[0409] Binding of the compound is detected and the dissociation constant K of the test compound to the immobilized E3 ligase is determined. D Compound concentration-response curves were recorded to obtain the . Compounds were tested at final concentrations of up to 20 μM in assay buffer, typically in 10-point dilutions, and flowed over the chip at 30 μL / min. The contact time for each cycle included 90 seconds for compound association and 200 seconds for dissociation. All test cycles were read as sensorgrams referenced to the sensor surface in the absence of target protein.

[0410] In the table below, K d Values ​​were expressed as +++ <100 nM, ++ 100–500 nM, and + >500 nM.

[0411] [Table 20]

[0412] [Table 21]

[0413] [Example 23] HTT degradation assay The compounds described herein are referred to as HTT-Exon1-polyQ nThe efficacy of HTT reduction was tested in human HeLa cells transiently overexpressing the protein. For HTT degradation experiments, HeLa cells were transiently transfected with the pcDNA3.1(+)-hHTT-E1mixQn-EGFP plasmid to transiently express HTT-Exon1 proteins with different polyQ lengths (HTT-exon1-Q23 / 73 / 145-EGFP). Two hours after transfection, cells were treated with test compounds at seven concentrations ranging from 0.01 μM to 10 μM (final assay concentrations) plus DMSO control. After 22 h of incubation with test compounds, cells were washed with 1× PBS and lysed in MSD lysis buffer (150 m m NaCl, 20 m m Tris ph 7.5, 1 m m EDTA, 1 m m EGTA, 1% Triton X-100, 1× phosphatase inhibitor cocktail 2, 1× phosphatase inhibitor cocktail 3, 1× protease inhibitor cocktail, 10 m m NaF, 1 m m PMSF) for 30 min on ice.

[0414] For analysis of HTT protein levels by the Meso Scale Discovery (MSD) assay, MSD384-well plates were coated with 10 μL per well of each coating antibody (soluble mHTT-Assay 6:2B7 (5 μg / mL), aggregated HTT-Assay 45:MW8, 4 μg / mL) in carbonate-bicarbonate coating buffer (15 mM Na2CO3, 35 mM NaHCO3, pH 9.6) overnight at 4°C. Plates were then washed three times with 35 μL per well of wash buffer (0.2% Tween-20 in PBS) and blocked with 35 μL per well of blocking buffer (2% probumin, 0.2% Tween-20 in PBS) for 1 hour at room temperature with end-over-end shaking.

[0415] For the mHTT aggregate-specific MSD assay, cell lysates were diluted to a final concentration of 1 mg / ml total protein in blocking buffer. For the soluble mHTT MSD assay, cell lysates were first diluted to a concentration of 0.2 mg / ml total protein in lysis buffer and then further diluted to a concentration of 0.1 mg / ml total protein in blocking buffer.

[0416] After an additional washing step, 10 μL per sample was transferred to each well of the antibody-coated MSD plate and incubated for 1 hour at room temperature with shaking. After discarding the sample and 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 for 1 hour at room temperature with shaking. After three washes with wash buffer, 35 μL of Read Buffer T with surfactant (Meso Scale Discovery) was added to each well. The plate was imaged on a Sector Imager 6000 (Meso Scale Discovery) according to the manufacturer's instructions and the recommended settings for 384-well plates. The resulting readout is the MSD signal intensity for each well. Background values ​​were subtracted from each sample. Relative mHTT levels were normalized to the DMSO-only control sample, which contained the highest mHTT protein load.

[0417] The reduction of soluble and aggregated mHTT Exon1-Q73 levels by compound 1 was confirmed by MSD assay (Figures 1A, 1B, and 2). Compound 10, which contains the inactive enantiomer of the ligase-binding domain, was found to be less active.

[0418] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0419] The invention illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations not specifically described herein. Thus, for example, terms such as "comprising," "including," "containing," etc., shall be read expansively and without limitation. In addition, the terms and expressions employed herein are used as terms of description and not of limitation, and the use of such terms and expressions is not intended to exclude any equivalents of the properties shown and described, or portions thereof, but it is recognized that various modifications are possible within the scope of the invention as claimed.

[0420] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety to the same extent as if each were individually incorporated by reference. In case of conflict, the present specification, including definitions, will control.

[0421] [Sequence table] SEQUENCE LISTING <110> CHDI FOUNDATION, INC. <120> COMPOUNDS FOR TARGETING MUTANT HUNTINGTIN PROTEIN AND USES THEREOF <130> PA24-549 <150> US 62 / 810,213 <151> 2019-02-25 <160> 13 <170> PatentIn version 3.5 <210> 1 <211> 19 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic peptide" <400> 1 Thr Phe Phe Tyr Gly Gly Ser Arg Gly Lys Arg Asn Asn Phe Lys Thr 1 5 10 15 Glu Glu Tyr <210> 2 <211> 23 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic peptide" <400> 2 Thr Glu Glu Leu Arg Val Arg Leu Ala Ser His Leu Arg Lys Leu Arg 1 5 10 15 Lys Arg Leu Leu Arg Asp Ala 20 <210> 3 <211> 18 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic peptide" <220> <221> MISC_FEATURE <222> (1)..(1) <223> Xaa is N-acetyl-leucine <220> <221> MISC_FEATURE <222> (18)..(18) <223> Xaa is C-terminal amidated leucine <400> 3 Xaa Arg Lys Leu Arg Lys Arg Leu Leu Leu Arg Lys Leu Arg Lys Arg 1 5 10 15 Leu Xaa <210> 4 <211> 38 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polypeptide" <400> 4 Ser Val Ile Asp Ala Leu Gln Tyr Lys Leu Glu Gly Thr Thr Arg Leu 1 5 10 15 Thr Arg Lys Arg Gly Leu Lys Leu Ala Thr Ala Leu Ser Leu Ser Asn 20 25 30 Lys Phe Val Glu Gly Ser 35 <210> 5 <211> 12 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic peptide" <220> <221> MISC_FEATURE <222> (12)..(12) <223> Xaa is C-terminal amidated proline <400> 5 Thr His Arg Pro Pro Met Trp Ser Pro Val Trp Xaa 1 5 10 <210> 6 <211> 8 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic peptide" <220> <223> cycle <220> <221> MISC_FEATURE <222> (1)..(1) <223> Xaa is N-acetyl-cysteine <400> 6 Xaa Met Pro Arg Leu Arg Gly Cys 1 5 <210> 7 <211> 20 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic peptide" <400> 7 Thr Trp Pro Lys His Phe Asp Lys His Thr Phe Tyr Ser Ile Leu Lys 1 5 10 15 Leu Gly Lys His 20 <210> 8 <211> 12 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic peptide" <400> 8 Thr Gly Asn Tyr Lys Ala Leu His Pro His Asn Gly 1 5 10 <210> 9 <211> 30 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polypeptide" <400> 9 Tyr Gln Gln Ile Leu Thr Ser Met Pro Ser Arg Asn Val Ile Gln Ile 1 5 10 15 Ser Asn Asp Leu Glu Asn Leu Arg Asp Leu Leu His Val Leu 20 25 30 <210> 10 <211> 29 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic peptide" <400> 10 Tyr Thr Ile Trp Met Pro Glu Asn Pro Arg Pro Gly Thr Pro Cys Asp 1 5 10 15 Ile Phe Thr Asn Ser Arg Gly Lys Arg Ala Ser Asn Gly 20 25 <210> 11 <211> 36 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polypeptide" <220> <221> MISC_FEATURE <222> (1)..(1) <223> Xaa is N-acetyl-valine <220> <221> MISC_FEATURE <222> (36)..(36) <223> Xaa is a PEG4-Cholesterol ester of isoleucine <400> 11 Xaa Ala Leu Asp Pro Ile Asp Ile Ser Ile Val Leu Asn Lys Ile Lys 1 5 10 15 Ser Asp Leu Glu Glu Ser Lys Glu Trp Ile Arg Arg Ser Asn Lys Ile 20 25 30 Leu Asp Ser Xaa 35 <210> 12 <211> 32 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polypeptide" <220> <221> MISC_FEATURE <222> (1)..(1) <223> Xaa is N-acetyl-valine <220> <221> MISC_FEATURE <222> (32)..(32) <223> Xaa is a PEG4-Cholesterol ester of lysine <400> 12 Xaa Asn Lys Lys Ile Glu Glu Ile Asp Lys Lys Ile Glu Glu Leu Asn 1 5 10 15 Lys Lys Leu Glu Glu Leu Glu Lys Lys Leu Glu Glu Val Asn Lys Xaa 20 25 30 <210> 13 <211> 36 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polypeptide" <220> <221> MISC_FEATURE <222> (1)..(1) <...

Claims

1. Compounds of formula (I) WL-ULM (I) or a pharma- ceutically acceptable salt, stereoisomer, mixture of stereoisomers, or isotopically enriched analogue thereof. (In the formula, W is a compound that targets mutant huntingtin protein (mHTT); L is a bond or a linking moiety optionally substituted with B; ULM is a moiety that targets E3 ubiquitin ligases. B is a moiety that crosses the blood-brain barrier and / or enhances cell permeability; However, the compound 【Chemistry 1】 (Provided that it is not.)

2. 2. The compound of claim 1, wherein the ULM is a moiety that targets mouse double minute 2 homolog (MDM2), cellular inhibitor of apoptosis protein 1 (cIAP1), cereblon (CRBN), or von Hippel-Lindau (VHL).

3. 2. The compound of claim 1, wherein the ULM is a moiety that targets VHL ligase.

4. 2. The compound of claim 1, wherein the ULM is a moiety that targets cereblon ligase.

5. 2. The compound of claim 1, wherein the ULM is a moiety that targets cellular inhibitor of apoptosis protein 1 (cIAP1).

6. ULM 【Chemistry 2】 (In the formula, R 40 is hydrogen or C 1～6 (It is alkyl) 2. The compound of claim 1, selected from:

7. R 40 7. The compound of claim 6, wherein is hydrogen.

8. ULM 【Chemistry 3】 【change】 2. The compound of claim 1,

9. W is a compound of formula (A) 【Chemistry 4】 (In the formula, The point of attachment of W to L-ULM is any substitutable atom of formula (A); L 1 is -CH=CH- or L 1 does not exist, R 1 is selected from phenyl or heteroaryl, each of which is Cyano, Hello, Heteroaryl, Lower alkyl, lower alkyl substituted with 1 or 2 substituents independently selected from lower alkoxy substituted with heteroaryl; -C(O)O-lower alkyl, Hydroxyl, lower alkynyloxy, lower alkoxy, Hello, Heterocycloalkyl, Heteroaryl, heteroaryl substituted with lower alkoxy; optionally substituted amino; Heteroaryl-substituted alkyl, and Alkyl substituted with heteroaryl substituted with lower alkoxy Lower alkoxy substituted with 1 or 2 substituents independently selected from and optionally substituted with 1, 2 or 3 groups independently selected from or R 1 is a phenyl substituted with two groups which, together with the carbon atom to which they are attached, form a heterocycloalkenyl ring, said phenyl being Hello, Heteroaryl, and Optionally substituted amino and optionally further substituted with a substituent selected from L 2 -N(R 4 )- or L 2 does not exist, R 2 teeth, hydrogen, Lower alkyl, and Lower alkyl substituted with lower alkoxy, amino, (alkyl)amino, (dialkyl)amino or hydroxy is selected from Each time it appears, R 3 teeth Hello, Cyano, Lower alkoxy, lower alkyl optionally substituted with amino, (alkyl)amino or di(alkyl)amino, and Ethynyl optionally substituted with tri(alkyl)silyl are independently selected from R 4 is hydrogen or lower alkyl; m is 0, 1 or 2.

9. The compound according to any one of claims 1 to 8, wherein

10. W is a compound of formula (B) 【Chemistry 5】 (In the formula, The point of attachment of W to L-ULM is any substitutable atom of formula (B); Z 1 , Z 2 , Z 3 and Z 4 is Z 1 , Z 2 , Z 3 and Z 4 are independently selected from CH and N, with the proviso that at least two of are CH; R 5 is heteroaryl, heterocycloalkenyl, or heterocycloalkyl, 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; or R 5 is phenyl optionally substituted with one or two groups independently selected from cyano, heteroaryl, halo, phenoxy, benzyloxy, heteroaryl, amino, lower alkyl optionally substituted with (alkyl)amino or di(alkyl)amino, lower alkoxy, optionally substituted amino, di(alkyl)aminocarbonyl, alkylaminocarbonyl, and aminocarbonyl; L 3 is -O-, and L 4 CR 8 R 9 ) p -or-(CR 8 R 9 ) p -O-, or L 3 Ha-NR 10 - and L 4 is -C(O)- or -(R 8 R 9 ) p -or- L 3 Ha-NR 10 - and L 4 is -C(O)(O)(R 8 R 9 ) p -or- L 3 Ha-NR 10 - and L 4 -C(O)(R 8 R 9 ) p (O)-, or L 3 Ha-NR 10 - and L 4 -C(O)(R 8 R 9 ) p -or- L 3 Ha-NR 10 - and L 4 -C(O)CR 8 =CR 9 -or- L 3 is -C(O)-, and L 4 Ha-NR 10 -or- L 3 Is -(R 8 R 9 ) p - and L 4 Ha-NR 10 -, -C(O)- or -O-; or L 3 does not exist, and L 4 does not exist, or L 3 L 4 together with -CH=CH-, -C≡C- or heterocyclylene; L 5 is -CH=CH-, or L 5 does not exist, R 6 is selected from heterocycloalkyl, aryl, and heteroaryl, each of which is -OC(O)-R 11 、 -C(O)O-R 11 、 amino, Hello, Haloalkyl, Phenyl, Heteroaryl, Cyano, (lower alkyl)thio, Phenoxy, Phenoxymethyl, Heteroaryloxy, heteroaryloxy substituted with lower alkyl; Hydroxyl, lower alkenyloxy, Lower alkoxy, lower alkoxy, lower alkoxy substituted with amino, (alkyl)amino, (dialkyl)amino, heterocycloalkyl, heteroaryl or halo; Lower alkyl, and Amino, (alkyl)amino, (dialkyl)amino, lower alkyl substituted with hydroxyl or lower alkoxy and optionally substituted with 1 or 2 groups selected from X 1 is NR 12 , O or S; Y 1 is CR 12 or N, R 10 is hydrogen or lower alkyl; R 12 is hydrogen, halo, cyano or lower alkyl; Each R 7 is independently selected from lower alkyl, lower alkoxy, and halo; R 11 is lower alkyl, Each R 8 is independently selected from hydrogen, hydroxyl, trifluoromethyl, and lower alkyl; Each R 9 is independently selected from hydrogen and lower alkyl; n is 0 or 1, p is 0, 1 or 2.

9. The compound according to any one of claims 1 to 8, wherein

11. W is a compound of formula (B)(i) 【Chemistry 6】 (wherein the wavy line represents the point of attachment to L of L-ULM) 11. The compound of claim 10,

12. W is a compound of formula (B)(i)(a) 【Chemistry 7】 (wherein the wavy line represents the point of attachment to L of L-ULM) 12. The compound of claim 11, wherein

13. W is a compound of formula (B)(ii) 【Chemistry 8】 (wherein the wavy line represents the point of attachment to L of L-ULM) 11. The compound of claim 10,

14. W is a compound of formula (B)(ii)(a) 【Chemistry 9】 (wherein the wavy line represents the point of attachment to L of L-ULM) 14. The compound of claim 13,

15. R 5 is heteroaryl optionally substituted with 1 or 2 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.

16. R 5 is heterocycloalkenyl optionally substituted with 1 or 2 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.

17. R 5 is heterocycloalkyl optionally substituted with 1 or 2 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.

18. R 6 is 5-6 membered 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 lower alkoxy substituted with halo; lower alkyl, and lower alkyl substituted with amino, (alkyl)amino, (dialkyl)amino, hydroxyl, or lower alkoxy.

19. W is a compound of formula (C) 【Chemistry 10】 (In the formula, The point of attachment of W to L-ULM is any substitutable atom of formula (C); X 2 (CR 16 =CR 16 ), O, NH or S; Y 2 is CR 16 or N, Each R 16 is independently selected from hydrogen, halo, cyano, and lower alkyl; Z 1 , Z 2 , Z 3 and Z 4 is Z 1 , Z 2 , Z 3 and Z 4 are independently selected from CH and N, with the proviso that at least two of are CH; R 13 is aryl, heteroaryl, or heterocycloalkyl, each of which is optionally substituted with 1 or 2 groups independently selected from alkynyl, heteroaryl, cyano, optionally substituted amino, halo, and lower alkyl optionally substituted with optionally substituted amino; L 6 is absent or is C(O)O, O or NR 17 and R 17 is hydrogen or lower alkyl; L 7 (CH 2 ) q and R 14 is 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 together with any intervening atoms form a 5- to 7-membered heterocycloalkyl ring; z is 0 or 1; q is 0, 1 or 2.

9. The compound according to any one of claims 1 to 8, wherein

20. W is a compound of formula (D) 【Chemistry 11】 (In the formula, The point of attachment of W to L-ULM is any substitutable atom of formula (D); Z 1 , Z 2 , Z 3 and Z 4 is Z 1 , Z 2 , Z 3 and Z 4 are independently selected from CH and N, with the proviso that at least two of are CH; R 18 is aryl, heteroaryl, or heterocycloalkenyl, each of which is optionally substituted with 1 or 2 groups independently selected from alkynyl, heteroaryl, cyano, optionally substituted amino, halo, lower alkyl, and lower alkyl substituted with optionally substituted amino; L 8 is O or NR 21 and R 21 is hydrogen or lower alkyl; L 9 (CH 2 ) x and R 19 is hydrogen, aryl, aryl substituted with hydroxyl or lower alkoxy, heteroaryl, and heteroaryl substituted with hydroxyl or lower alkoxy; Each R 20 is independently selected from lower alkyl, lower alkoxy, halo, and oxo (as substituents on a heterocycloalkyl ring); x is 0, 1 or 2; (y is 0 or 1) 9. The compound according to any one of claims 1 to 8, wherein

21. W is a compound of formula (E) 【Chemistry 12】 (In the formula, The point of attachment of W to L-ULM is any substitutable atom of formula (E); J is C(=O) or -CH 2 - and X 3 is S or N, Y 3 is CH or N, Z 5 is CH or N, Q is N or S; Each time it appears, R 23 is independently selected from halo, lower alkoxy, hydroxy, aryl, heteroaryl, cycloalkoxy, and lower alkyl, and lower alkoxy, cycloalkoxy, lower alkyl, aryl, or heteroaryl is independently selected from lower alkoxy, alkenyl, -NR 24 R 25 each optionally substituted with 1, 2, or 3 groups independently selected from halo, and heteroaryl optionally substituted with 1 to 3 lower alkoxy; R 21 is hydrogen or lower alkyl; R 22 is alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, or heteroaralkyl, each of which is selected from the group consisting of hydroxy, lower alkoxy, or lower alkoxy optionally substituted with halo, lower alkyl optionally substituted with halo, halo, heteroaryl, -(CH 2 ) t NR 24 R 25 , oxo, cyano, and -C(O)-NR 24 R 25 or R 21 and R 22 taken together with the nitrogen to which they are attached represent hydroxy, lower alkoxy, lower alkyl, halo, and -C(O)-NR 24 R 25 forming a heterocycloalkyl ring optionally substituted with 1, 2 or 3 groups independently selected from t is 0, 1 or 2; Each R 24 is independently selected from hydrogen or lower alkyl; Each R 25 are independently selected from hydrogen or lower alkyl; or R 24 and R 25 taken together with the nitrogen to which they are attached represent hydroxy, lower alkoxy, lower alkyl, halo, or -C(O)-NR 26 R 27 forming a heterocycloalkyl ring optionally substituted with 1, 2 or 3 groups independently selected from Each R 26 are independently hydrogen or lower alkyl; Each R 27 are independently hydrogen or lower alkyl; s is 0, 1 or 2; r is 1 or 2) 9. The compound according to any one of claims 1 to 8, wherein

22. W is a compound of formula (E)(i) 【Chemistry 13】 (wherein the wavy line represents the point of attachment to L of L-ULM) 22. The compound of claim 21, wherein

23. R 21 is hydrogen and R 22 is aryl, aralkyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, or heteroaralkyl, each of which is selected from the group consisting of hydroxy, lower alkoxy, or lower alkoxy optionally substituted with halo, lower alkyl optionally substituted with halo, halo, heteroaryl, -(CH 2 ) t NR 24 R 25 , oxo, cyano, and -C(O)-NR 24 R 25 23. The compound of claim 21 or 22, optionally substituted with 1, 2 or 3 groups independently selected from:

24. W is a compound of formula (F) 【Chemistry 14】 (In the formula, X 3 is S or N, Y 3 is CH or N, Z 5 is CH or N, Q is N or S; R 28 is cyano, lower alkoxy, lower alkenyl, -NR 24 R 25 , halo, and heteroaryl optionally substituted with 1 to 3 lower alkoxy; Each R 24 is independently selected from hydrogen or lower alkyl; Each R 25 are independently selected from hydrogen or lower alkyl; or R 24 and R 25 taken together with the nitrogen to which they are attached represent hydroxy, lower alkoxy, lower alkyl, halo, or -C(O)-NR 26 R 27 forming a heterocycloalkyl ring optionally substituted with 1, 2 or 3 groups independently selected from Each R 26 are independently hydrogen or lower alkyl; Each R 27 are independently hydrogen or lower alkyl; The wavy line represents the attachment point of W to L in L-ULM.

9. The compound according to any one of claims 1 to 8, wherein

25. R 28 is cyano, lower alkoxy, lower alkenyl, -NR 24 R 25 25. The compound of claim 24, which is a bicyclic heteroaryl optionally substituted with 1, 2, or 3 groups independently selected from heteroaryl optionally substituted with 1 to 3 lower alkoxy.

26. R 28 Cyano and -NR 24 R 25 25. The compound of claim 24, which is a bicyclic heteroaryl optionally substituted with 1 or 2 groups independently selected from:

27. L is a linking moiety optionally substituted with B; ULM 【Chemistry 15】 【change】 and W (i) A compound of formula (A) 【Chemistry 16】 (ii) A compound of formula (B) 【Chemistry 17】 or (iii) a compound of formula (E) 【Chemistry 18】 22. The compound according to any one of claims 9, 10 and 21, wherein

28. 27. The compound of any one of claims 1 to 26, wherein L is a bond.

29. 27. The compound of any one of claims 1 to 26, wherein L is a linking moiety optionally substituted with B.

30. the linking moiety is alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene; Each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene can optionally include arylene, heteroarylene, cycloalkylene, or heterocycloalkylene; Further, each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene may be selected from the group consisting of oxo, halo, C 1～4 Alkyl, C 1～4 Alkoxy and C 1～4 29. The compound of claim 27 or 28, optionally substituted with 1 to 5 substituents independently selected from haloalkyl.

31. The linking moiety has the formula -G 1 -((CH 2 ) a -G 2 ) c -(CH 2 ) b -G 3 - (In the formula, G 1 , G 2 and G 3 each independently represents a bond, -NR 28 -, -O-, -S(O) 0～2 -, -NR 28 C(O)-, -C(O)NR 28 -, -NR 28 S(O) 2 -, -S(O) 2 NR 28 -, -CR 29 =N-NR 28 -, -NR 28 -N=CR 29 -, or -C(O)-, alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene, and each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene is selected from the group consisting of oxo, halo, C 1～4 Alkyl, C 1～4 Alkoxy and C 1～4 is optionally substituted independently with 1 to 5 substituents independently selected from haloalkyl; Each R 28 are independently hydrogen, C 1～4 Alkyl, C 1～4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; R 29 is C 1～4 Alkyl, C 1～4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; a and b are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8; c is an integer between 0 and 20, The linking moiety is, on a substitutable atom, (-G 4 -(CH 2 ) d -G 5 -) e -B is sometimes replaced by G 4 and G 5 each independently represents a bond, -NR 28 -, -O-, -S(O) 0～2 -, -NR 28 C(O)-, -C(O)NR 28 -, -NR 28 S(O) 2 -, -S(O) 2 NR 28 -, -CR 29 =N-NR 28 -, -NR 28 -N=CR 29 -, or -C(O)-, alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene, and each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene is selected from the group consisting of oxo, halo, C 1～4 Alkyl, C 1～4 Alkoxy and C 1～4 is optionally substituted independently with 1 to 5 substituents independently selected from haloalkyl; d and e are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8.

30. The compound of claim 29,

32. The linking moiety has the formula -G 1 -((CH 2 ) a -G 2 ) c -(CH 2 ) b -G 3 - (In the formula, G 1 , G 2 and G 3 each independently represents a bond, -NR 28 -, -O-, -S(O) 0～2 -, -NR 28 C(O)-, -C(O)NR 28 -, -NR 28 S(O) 2 -, -S(O) 2 NR 28 -, -CR 29 =N-NR 28 -, -NR 28 -N=CR 29 -, or -C(O)-, alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene, and each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene is selected from the group consisting of oxo, halo, C 1～4 Alkyl, C 1～4 Alkoxy and C 1～4 is optionally substituted independently with 1 to 5 substituents independently selected from haloalkyl; Each R 28 are independently hydrogen, C 1～4 Alkyl, C 1～4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; R 29 is C 1～4 Alkyl, C 1～4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; a and b are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8; where c is an integer between 0 and 20.

30. The compound of claim 29,

33. 33. The compound of any one of claims 1 to 27 and 29 to 32, wherein B is a carrier peptide, cholesterol or a carrier peptide conjugated to cholesterol.

34. 33. The compound of any one of claims 1 to 27 and 29 to 32, wherein B is Angiopep2, ApoE-I, ApoE-II, ApoB, THR, peptide-22, L57, TGN, leptin 30, RVG29, Nipah virus env. HR region conjugated to cholesterol, Newcastle disease virus conjugated to cholesterol, or measles virus peptide conjugated to cholesterol.

35. A compound selected from Table 2 or a pharma- ceutically acceptable salt, stereoisomer, mixture of stereoisomers, or isotopically enriched analogue thereof.

36. 36. A pharmaceutical composition comprising any one of claims 1 to 35 and a pharma- ceutically acceptable excipient or carrier.

37. 37. A method for inducing degradation of mHTT, comprising administering a therapeutically effective amount of a compound of claims 1 to 35 or a pharmaceutical composition of claim 36.

38. 37. A method for treating Huntington's disease, comprising administering a therapeutically effective amount of a compound of claims 1 to 35 or a pharmaceutical composition of claim 36.

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