Compounds and probes for imaging huntingtin protein

Abstract

Provided herein are certain compounds of formula (I) and imaging agents useful for detecting conditions or disorders associated with protein aggregation, compositions thereof, and methods of their use. [Formula 1] TIFF2023507185000104.tif35149

Description

[Technical Field]

[0001] Cross-reference to related patent applications This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 62 / 950,020, filed December 18, 2019, which is incorporated herein by reference in its entirety.

[0002] Provided herein are compounds and imaging agents useful for detecting conditions or disorders associated with protein aggregation, compositions thereof, and methods of their use. [Background technology]

[0003] The advent of molecular imaging techniques such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) has enabled the measurement of molecular and cellular mechanisms throughout the body in preclinical and clinical settings. Such measurements have expanded diagnostic utility, and their use to assess treatment response and aid drug development is rapidly expanding. The introduction of high-resolution molecular imaging techniques is seen by many experts as a major breakthrough.

[0004] PET involves the administration of a positron-emitting radionuclide tracer to a subject, followed by detection of the positron-emitting (annihilation) event within the body. Radionuclide tracers typically consist of a targeting molecule with one or more positron-emitting radionuclides incorporated therein.

[0005] Molecular probes labeled with positron-emitting radionuclides and related PET imaging assays are being developed to target, detect, visualize, and quantify a variety of extracellular and intracellular molecules and various disease-related processes.

[0006] Huntington's disease (HD) is an inherited, progressive neurodegenerative disorder characterized by motor, cognitive, and psychiatric impairments and neurodegeneration, with brain atrophy beginning in the striatum and cortex and extending to other subcortical brain regions. Polyglutamate domain expansions are thought to cause conformational changes in the huntingtin (HTT) protein, which can lead to the formation of aggregates. HD has a worldwide prevalence of 5-10 cases per 100,000, making it the most common inherited neurodegenerative disorder.

[0007] As with other medical conditions, treatment of HD ideally begins at or before the first signs of disease. Therefore, early indications of disease are highly desirable. Summary of the Invention [Problem to be solved by the invention]

[0008] In view of the central role of the accumulation of aggregated forms of proteins in the pathogenesis of neurodegenerative conditions, including HD, there is a need for molecules that bind to such proteins with high sensitivity and specificity, enabling molecular imaging. [Means for solving the problem]

[0009] The present invention relates to compounds useful for imaging huntingtin proteins. Some embodiments have the formula (I):

[0010] [ka] [In the formula, Z 1 and Z 2 are each independently CH, or Z 1 and Z 2 one of which is N and the other is CH; Z 3 is N or CH; L 1 -OC 1~4 Alkylene, -OC 1~4Alkylene-O- or -N(R 4 )C(=O)-; X 1 and X 2 One of them is NL 2 -R 2 and the other is CH2; X 3 is CH2 or -O-CH2-; L 2 is -(CH2) n -, -C(=O)-, -C(=O)NH-, -C(=O)(O)-(CH2) n or -S(=O)2; n is 0, 1, or 2; R 1 are aryl or heteroaryl, and are halogen, haloalkyl, hydroxy, alkyl, alkoxy, haloalkoxy, and —N(R 4 ) optionally substituted with 1 or 2 substituents independently selected from: R 2 is aryl, alkyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl, each of which is selected from the group consisting of alkyl optionally substituted with halogen, haloalkyl, hydroxy, alkenyl, or alkoxy, alkoxy optionally substituted with alkenyl or alkoxy, haloalkoxy, heteroaryl, and —N(R 4 ) optionally substituted with 1 or 2 substituents independently selected from: p is 0, 1 or 2; Each R 3 is independently C 1~4 alkyl, or two R on the same carbon 3 forms an oxo, where R 3 teeth,

[0011] [ka] one or more ring carbon atoms of which may be substituted; Each R 4 are independently H or C 1-4 alkyl] or an isotopically labeled analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof.

[0012] Also provided are additional compounds described herein. In some embodiments, a compound selected from Table 1, or an isotopically labeled analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof, is provided.

[0013] Also provided are pharmaceutical compositions comprising a compound described herein or an isotopically labeled analog thereof, a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers, and a pharmaceutically acceptable carrier.

[0014] Also provided are imaging agents comprising the compounds described herein, wherein the compounds are labeled with one or more positron-emitting radionuclides. In some embodiments, provided are imaging agents comprising the compounds described herein, wherein the compounds are labeled with one or more positron-emitting radionuclides. In some embodiments, provided are imaging agents comprising the compounds described herein, wherein the compounds are: 11 C. 13 N, 15 O and 18 Imaging agents labeled with one or more positron-emitting radionuclides selected from F are provided. In some embodiments, the compound is 11 C. 13 N, 15 O and 18 F.

[0015] Also provided are methods of producing a diagnostic image, e.g., a positron emission tomography (PET) image, in an individual, comprising administering an effective amount of a compound described herein or an imaging agent comprising a compound described herein, and producing an image of a body part or region of the individual.

[0016] Also provided are methods for detecting the presence or absence of an aggregation-prone protein, such as huntingtin protein (HTT protein), in diagnostic imaging to detect the presence or absence of a pathological process. In some embodiments, the pathological process can be a neurodegenerative disease selected from Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, prion disease, and spinocerebellar ataxia. In some embodiments, the neurodegenerative disease is Huntington's disease. DETAILED DESCRIPTION OF THE INVENTION

[0017] 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 rather is provided as a description of exemplary embodiments.

[0018] As used herein, the following words, phrases, and symbols are generally intended to have the meanings set forth below, except to the extent that the context in which they are used herein indicates otherwise.

[0019] A dash ("-") that is not between two letters or two symbols is used to indicate a point of attachment for a substituent, for example, -C(O)NH2 is attached through a carbon atom.

[0020] "Optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes examples where the event or circumstance occurs and examples where it does not occur. An "optionally substituted" group is one that may be unsubstituted with the group shown or defined. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl," as defined below. Those of skill in the art will understand that with respect to any group containing one or more substituents, it is not intended that such group introduce any substitution or substitution pattern that is sterically impractical and / or inherently unstable.

[0021] "Alkyl" includes straight- and branched-chain hydrocarbon groups having the designated number of carbon atoms, usually 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- and branched-chain alkyls of 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, and the like. When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be included, so, for example, "butyl" includes n-butyl, sec-butyl, isobutyl, and t-butyl, and "propyl" is meant to include n-propyl and isopropyl.

[0022] The term "alkylene" encompasses straight- and branched-chain diradical hydrocarbon groups 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 or 1 to 4 carbon atoms. For example, a C1 alkylene is a methylene group. Additional examples of C1-C4 alkylene include 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 1,1-butylene, 1,2-butylene, 1,3-butylene, 1,4-butylene, 2-methyl-1,2-propylene, and 2-methyl-1,3-propylene.

[0023] "Alkoxy" means an alkyl group of the 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, etc. An alkoxy group will typically have 1 to 6 carbon atoms attached through an oxygen bridge.

[0024] "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 may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some instances, both rings in a polycyclic aryl group are aromatic (e.g., naphthyl). In other instances, a polycyclic aryl group may contain 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 carbocyclic 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) is 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) is not considered an aryl group. Similarly, a 1,2,3,4-tetrahydroquinolin-8-yl group (where the moiety is attached to the parent structure via 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 via a non-aromatic nitrogen atom) is not considered an aryl group. However, the term "aryl" does not encompass or overlap with "heteroaryl," as defined herein, regardless of the point of attachment (e.g., both quinolin-5-yl and quinolin-2-yl are heteroaryl groups). In some examples, aryl is phenyl or naphthyl. In certain examples, aryl is phenyl.

[0025] Divalent radicals formed from substituted benzene derivatives and having a free valence at a ring atom are named substituted phenylene radicals. Divalent radicals derived from monovalent polycyclic hydrocarbon radicals by removing one hydrogen atom from the carbon atom having the free valence, whose names end in "-yl", are named by adding "-ydene" to the name of the corresponding monovalent radical; for example, a naphthyl group with two points of attachment is called a naphthylidene.

[0026] "Cycloalkyl" refers to a saturated or partially unsaturated carbocyclic ring having the indicated number of carbon atoms, e.g., 3 to 10, 3 to 8, or 3 to 6 ring carbon atoms. Cycloalkyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl, as well as bridged spirocyclic and caged ring groups (e.g., norbornane, bicyclo[2.2.2]octane). In addition, one ring of a polycyclic cycloalkyl group may be aromatic, provided that the polycyclic cycloalkyl group is 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. That is, it is considered an aryl group. "Cycloalkenyl" refers to a partially unsaturated carbocyclic ring that is not aryl as defined herein.

[0027] The term "halo" includes fluoro, chloro, bromo and iodo, and the term "halogen" includes fluorine, chlorine, bromine and iodine.

[0028] The term "haloalkyl" refers to an alkyl group where the alkyl is substituted with from one halogen to fully substituted ("perhaloalkyl") groups. A fully substituted haloalkyl is a group of formula C n L 2n+1 where L is a halogen and "n" is 1 to 6, e.g., 1, 2, 3, or 4; when more than one halogen is present, they may be the same or different and are selected from the group consisting of F, Cl, Br, and I, e.g., F. In some embodiments, haloalkyl is C 1~4 Haloalkyl or C 1~6 Haloalkyl. C 1~4Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the like.

[0029] The term "hydroxyalkyl" refers to an alkyl group, as defined herein, where the alkyl is substituted with 1, 2, 3, or 4 hydroxy groups, one hydroxy group for each carbon atom. Examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl, 3-hydroxypropyl, 2-hydroxy-sec-butyl, 3,4-dihydroxybutyl, and the like.

[0030] The term "haloalkoxy" means a haloalkyl attached to the parent structure through an oxygen atom. Examples include, but are not limited to, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, and the like.

[0031] "Heteroaryl" refers to an aromatic ring (e.g., a 5- to 12-membered or 5- to 10-membered heteroaryl) containing 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. A heteroaryl group does not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in a heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in a heteroaryl group does not exceed 1. Unless otherwise specified, a heteroaryl group may be attached to the parent structure by a carbon or a nitrogen atom, valence permitting. 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 may be in any oxidized state (i.e., N) when the nature of the adjacent atoms and groups permits. + -O - In addition, when sulfur is present in a heteroaryl ring, it may be present in an oxidized state (i.e., S+ -O - or SO2). Heteroaryl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic).

[0032] In some examples, the heteroaryl group is monocyclic. Examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-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.

[0033] In some cases, all 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-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[5,4-c]pyridine 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.

[0034] In other examples, a polycyclic heteroaryl group may contain 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, 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (the moiety is attached to the parent structure through an aromatic carbon atom) is considered a heteroaryl group, while 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (the moiety is attached to the parent structure through a non-aromatic carbon atom) is not considered a heteroaryl group.

[0035] "Heterocycloalkyl" refers to a non-aromatic, saturated or partially unsaturated ring having the indicated number of atoms (e.g., a 3- to 10- or 3- to 7-membered heterocycloalkyl) 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. The term "heterocycloalkyl" includes heterocycloalkenyl groups (i.e., heterocycloalkyl groups having at least one double bond) and may contain one or more oxo (=O) or N-oxide (-O), whether or not oxo is named as a substituent. -) moieties. Heterocycloalkyl groups can be monocyclic (i.e., heteromonocyclic) or polycyclic (including, for example, bicyclic (i.e., heterobicyclic), spirocyclic, and bridged ring systems). Thus, the definition of heterobicyclic encompasses heteromonocyclic rings that are 1,1-disubstituted with a cycloalkyl or heteromonocyclic group, as well as ring systems in which a heteromonocyclic ring is 1,2- or 1,3-fused to another cycloalkyl or heteromonocyclic ring (where a carbon or nitrogen atom can form the ring junction (where this structure is chemically feasible)), as well as ring systems in which a heteromonocyclic ring has a C1-C2 alkyl bridge, and ring systems in which a heteromonocyclic ring is 1,2-fused to an aromatic or heteroaromatic ring, provided that the moiety is attached to the parent structure through a non-aromatic carbon or nitrogen atom.

[0036] Examples of monocyclic heterocycloalkyl (ie, heteromonocyclic) groups include oxiranyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, piperidin-2-one-1-yl, and thiomorpholinyl.

[0037] Examples of C6 heterobicyclyl groups include 3-azabicyclo[3.1.0]hexan-3-yl.

[0038] C8-C with aromatic ring 10 Examples of heterobicyclyl groups include indolin-1-yl, isoindolin-2-yl, 1,2,3,4-tetrahydroquinolin-2-yl, 3,4-dihydroquinolin-1(2H)-yl, and 7,8-dihydro-1,6-naphthyridin-6(5H)-yl.

[0039] Examples of heterobicyclyl ring systems containing spiro rings include 1-oxa-5-azaspiro[3.3]heptan-5-yl, 1-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 1,5-diazaspiro[3.3]heptan-1-yl, 1,6-diazaspiro[3.3]heptan-6-yl, 1,6-diazaspiro[3.3]heptan-1-yl, 2,6-diazaspiro[3.3]heptan-2-yl, ... 2,5-diazaspiro[3.4]octan-5-yl, 2,6-diazaspiro[3.4]octan-6-yl, 1-oxa-5-azaspiro[3.5]nonan-5-yl, 1-oxa-6-azaspiro[3.5]octan-5-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl, 1,5-diazaspiro[3.4]octan-5-yl, 1,6-diazaspiro[3.4]octan-6-yl, 2,5-diazaspiro[3.4]octan-5-yl, 2,6-diazaspiro[3.4]octan-6-yl, 1-oxa-5-azaspiro[3.5]nonan-5-yl, 1-oxa-6-azaspiro[3.5]nonan-5-yl 1-oxa-7-azaspiro[3.5]nonan-7-yl, 2-oxa-5-azaspiro[3.5]nonan-5-yl, 2-oxa-6-azaspiro[3.5]nonan-6-yl, 2-oxa-7-azaspiro[3.5]nonan-7-yl, 1,5-diazaspiro[3.5]nonan-5-yl, 1,6-diazaspiro[3.5]nonan-6-yl, 1,7-diazaspiro[3.5]nonan-7-yl, 2,5-diazaspiro[3.5]nonan-5-yl, 2,6-diazaspiro[3.5]nonan-6-yl, 2,7-diazaspiro [3.5]nonan-7-yl, 1-oxa-5-azaspiro[3.6]decan-5-yl, 1-oxa-6-azaspiro[3.6]decan-6-yl, 1-oxa-7-azaspiro[3.6]decan-7-yl, 2-oxa-5-azaspiro[3.6]decan-5-yl, 2-oxa-6-azaspiro[3.6]decan-6-yl, 2-oxa-7-azaspiro[3.6]decan-7-yl, 1,5-diazaspiro[3.6]decan-5-yl, 1,6-diazaspiro[3.6]decan-6-yl, 1,7-diazaspiro[3.6]decan-7-yl, 2,5-diazaspiro[3.6]decan-5-yl, 2,6-diazaspiro[3.6]decan-6-yl, and 2,7-diazaspiro[3.6]decan-7-yl.

[0040] Examples of heterobicyclyl ring systems containing a C1-C4 bridged alkylene include 2-azabicyclo[2.2.1]heptan-2-yl, 2-azabicyclo[3.2.1]octan-2-yl, 3-azabicyclo[3.2.1]octan-3-yl, and 6-azabicyclo[3.2.1]octan-6-yl.

[0041] When nitrogen is present in a heterocycloalkyl ring, it may be present in any oxidation 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 be present in any oxidized state (i.e., S + -O - or -SO2-). Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide.

[0042] "Solvate" refers to an association or complex of one or more solvent molecules with a compound described herein. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine.

[0043] A "prodrug" refers to any compound that releases an active parent drug according to the structures described herein in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds described herein are prepared by modifying functional groups present in the compounds described herein such that the modifications can be cleaved in vivo to release the parent compound. Prodrugs can be prepared by modifying functional groups present in the compounds described herein such that the modifications can be cleaved to the parent compound, either by routine manipulation or in vivo. Prodrugs include compounds described herein in which a hydroxy, amino, carboxyl, or sulfhydryl group in the compounds described herein is bonded to any group that can be cleaved in vivo to regenerate the free hydroxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives at a hydroxy group), amides (e.g., at an amino group), guanidines (e.g., at an amino group), and carbamates (e.g., N,N-dimethylaminocarbonyl at a hydroxy group) derived from functional groups in the compounds described herein. The preparation, selection, and use of prodrugs are discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series; "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985; and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is incorporated herein by reference in its entirety.

[0044] The term "substituted," as used herein, means that any one or more hydrogens on the designated atom or group have been replaced with a moiety 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 indicate 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 along with the core structure. For example, when (cycloalkyl)alkyl is listed as a possible substituent, it is understood that the point of attachment of this substituent to the core structure is in the alkyl portion.

[0045] The terms "substituted" alkyl, cycloalkyl, aryl, heterocycloalkyl, 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 , -SR b , guanidine (-NHC(=NH)NH2), guanidine (wherein one or more of the guanidine hydrogens is replaced with a C1-C4 alkyl group), -NR b R c , halo, cyano, oxo, nitro, -COR b , -CO2R b , -CONR b R c , -OC(O)R b , -OCO2R a , -OC(O)NR b R c , -N(R c )C(O)R b , -N(R c )CO2R a , -N(R c )CONR b R c , -S(O)R a , -SO2R a, -SO2NR b R c , and -N(R c )SO2R a each of which refers to an alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl group substituted by a substituent independently selected from: where 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, and 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; and wherein, in some embodiments, each C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl is selected from the group consisting of C1-C4 alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl-, —O-C4 alkyl, —O-C4 alkylphenyl, —C1-C4 alkyl-OH, —C1-C4 alkyl-O—C1-C4 alkyl, —O-C4 haloalkyl, halo, —OH, —NH, —C1-C4 alkyl-NH, —N(C1-C4 alkyl)(C1-C4 alkyl), —NH(C1-C4 alkyl), —N(C1-C4 alkyl)(C1-C4 alkylphenyl), —NH(C1-C4 alkylphenyl), cyano, nitro, oxo, —COH, —C(O)OC1-C4 alkyl, —CON (C1-C4 alkyl)(C1-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, -C(O)C1-C4 phenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1- Optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from C4 alkyl, -SO2(C1-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SON2NH2, -SON2NH(C1-C4 alkyl), -SON2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl), and -NHSO2(C1-C4 haloalkyl).

[0046] "Stereoisomer" refers to one of a series of compounds composed of the same atoms joined by the same bonds but having different three-dimensional structures and which are not interconvertible. The term "enantiomer" refers to one of a pair of stereoisomers that are non-superimposable mirror images of each other. A compound depicted as a single stereoisomer is intended to encompass a mixture of stereoisomers. In particular, asymmetric ("chiral") carbon centers may be enriched or racemic mixtures with respect to each such center in the compound.

[0047] The compounds described herein include, but are not limited to, their optical isomers, racemates, and other mixtures thereof. In such situations, single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished 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) or supercritical fluid chromatography (SFC) column. In addition, such compounds include Z- and E-forms (or cis- and trans-forms) of compounds with carbon-carbon double bonds. In cases where the compounds described herein exist in various tautomeric forms, the term "compound" is intended to include all tautomeric forms of the compound. Such compounds also include solid forms. Similarly, the term "salt" is intended to include all tautomeric forms of the compound and solid salt forms.

[0048] "Pharmaceutically acceptable salts" include salts with inorganic acids, such as hydrochlorides, phosphates, diphosphates, hydrobromides, sulfates, sulfinates, nitrates, and the like, as well as salts with organic acids, such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, and alkanoates such as acetate, HOOC-(CH2) q-COOH (wherein q is 0 to 4), and similar salts. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0049] In addition, if the compounds described herein are obtained as acid addition salts, 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 produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional methods for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that may be used to prepare non-toxic, pharmaceutically acceptable addition salts.

[0050] The present invention also encompasses "isotopically labeled analogs," which are the same as the compounds described herein except that one or more atoms have been replaced by atoms having atomic masses or mass numbers, or distributions thereof, different from those found in nature. The present invention also encompasses imaging agents comprising isotopically labeled analogs. All isotopically labeled variants described herein, whether radioactive or not, are intended to be encompassed within the scope of the present invention. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, e.g., 2 H (deuterium, D), 3 H (tritium, T), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125Isotopically labeled compounds of the present invention include, but are not limited to, I and the positron-emitting isotopes described herein. Substitution with heavier isotopes, such as deuterium, may confer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life). Isotopically labeled compounds of the present invention can generally be prepared by procedures similar to those described in the schemes and examples, for example, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. Isotopically labeled compounds (deuterated or tritiated compounds described herein) generally have an isotopic abundance at the labeled atom greater than that found in nature (e.g., found on Earth). In some embodiments, the isotopically labeled analogs described herein are deuterated or tritiated analogs. In some embodiments, deuterated analogs of the compounds described herein are provided. In some embodiments, tritiated analogs of the compounds described herein are provided.

[0051] The term "deuterated," as used herein alone or as part of a group, means that one or more hydrogen atoms in a compound or imaging agent are replaced with deuterium atoms, and the term "deuterated analog," as used herein alone or as part of a group, refers to a compound incorporating such a replacement. The term "tritiated," as used herein alone or as part of a group, means that one or more hydrogen atoms in a compound or imaging agent are replaced with tritium atoms, and the term "tritiated analog," as used herein alone or as part of a group, refers to a compound incorporating such a replacement. Deuterated or tritiated analogs can be fully or partially substituted analogs. In some embodiments, deuterated or tritiated analogs comprise fully or partially deuterium-substituted alkyl, aryl, or heteroaryl groups.

[0052] As used herein, the terms "group," "moiety," "radical," "substituent," and "fragment" are synonymous and are intended to indicate a portion of a molecule that can be attached to another portion of the molecule, for example, via a designated point of attachment or bond.

[0053] The term "active agent" is used to refer to a compound that has biological activity. In some embodiments, an "active agent" is a compound that has pharmaceutical utility or an isotopically labeled analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof. For example, an active agent may be an anti-neurodegenerative therapeutic agent.

[0054] The term "effective amount" refers to an amount sufficient to bring about a desired response in an individual or patient. In the context of the use of an imaging agent, an effective amount may be the amount required to produce an image having diagnostic or therapeutic utility. The term "therapeutically effective amount" refers to an amount that, when administered to a human or non-human patient, is effective to confer a therapeutic benefit, such as amelioration of symptoms, delay of disease progression, or prevention of disease; for example, a therapeutically effective amount may be an amount sufficient to reduce the symptoms of a disease described herein.

[0055] The term "huntingtin protein" or "HTT protein," as used herein, refers to the protein encoded by the human huntingtin gene (HTT gene), which is located on the short (p) arm of chromosome 4 at position 16.3. More precisely, the IT that encodes the HTT protein 15 The gene is located on chromosome 4 from base pair 3,076,407 to base pair 3,245,686.

[0056] The term "protein aggregation," as used herein, refers to the aggregation of proteins, which may be, for example, insoluble fibrillar amyloid comprising misfolded HTT protein molecules ("HTT protein aggregates") or misfolded β-amyloid protein molecules ("β-amyloid aggregates").

[0057] The term "imaging agent," as used herein, refers to a compound described herein that is labeled with one or more positron-emitting isotopes or radionuclides, or a composition comprising the labeled compound. A positron-emitter-labeled compound need only be enriched with a detectable isotope to the extent that it permits detection using a technique appropriate for the particular application.

[0058] The term "PET imaging" (also called positron emission tomography imaging), as used herein, refers to the use of positron emitter-labeled compounds to produce images of internal structures of the human or animal body.

[0059] The term "positron-emitting radionuclide," as used herein, refers to a radionuclide in which protons within the nucleus of the radionuclide emit positrons and electron neutrinos (ν e β refers to radioactive isotopes that exhibit a particular type of radioactive decay, called β decay, in which they are converted into neutrons while emitting positrons. Some examples of positron-emitting radionuclides include: 15 O. 13 N, 11 C. 18 F, 76 Br and 124 Contains I.

[0060] The term "labeled," as used herein, refers to a compound that is associated with one or more positron-emitting radionuclides. For example, the labeled compounds described herein may contain one or more positron-emitting radionuclides in which atoms in the molecule (including any indicated substituents) exist as positron-emitting isotopes.

[0061] The term "tomography," as used herein, refers to a segmental imaging technique in which the images can be viewed as a series of two-dimensional slices, either individually or together, or as a computer-generated three-dimensional display.

[0062] "Treatment" or "treating" means any treatment of a disease state in a patient; a) To prevent disease, i.e., to prevent the clinical signs of disease from appearing b) Inhibiting disease c) delaying or arresting the onset of clinical signs, and / or d) To alleviate the disease, i.e., to bring about a regression of clinical signs Includes.

[0063] "Subject" or "patient" refers to an animal, e.g., a mammal, who is or will be the object of treatment, observation, or experiment. The methods described herein can be useful in both human therapy and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is human.

[0064] The term "curie" (Ci) is a unit of measure of radioactivity and has its conventional meaning to those skilled in the art.

[0065] The term "diagnostic imaging," as used herein, refers to the use of electromagnetic radiation to produce images of internal structures of the human or animal body for diagnostic purposes.

[0066] A compound described herein refers to a compound of any of Formula (I), Formula (IIa), Formula (IIb), Formula (IIIa), Formula (IIIb) or Formula (IIIc), or an isotopically labeled analogue, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof, or a compound of the Examples, or a compound of Table 1 or a labeled isomer of such a compound described herein, or an imaging agent comprising such a compound or labeled compound.

[0067] It should be understood that certain features described herein that are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features described herein that are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. All combinations of embodiments relating to chemical groups represented by variables contained in Formula I, to the extent that such combinations result in stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity), are specifically embraced herein, as if each and every combination were individually and explicitly recited. Furthermore, all subcombinations of chemical groups recited in embodiments describing such variables, and all subcombinations of uses and medical applications described herein, are also specifically embraced herein, as if each and every subcombination of chemical groups and subcombinations of uses and medical applications were individually and explicitly recited. Furthermore, some embodiments include any combination of one or more additional agents disclosed herein, as if each and every combination were individually and explicitly recited.

[0068] List of Abbreviations and Acronyms

[0069] [Table 1] TIFF0007720847000004.tif242148TIFF0007720847000005.tif53154

[0070] compound The present invention relates to compounds useful for imaging huntingtin proteins. Some embodiments have the formula (I):

[0071] [ka] [In the formula, Z 1 and Z 2 are each independently CH, or Z 1 and Z 2 one of which is N and the other is CH; Z 3 is N or CH; L 1 -OC 1~4 Alkylene, -OC 1~4 Alkylene-O- or -N(R 4 )C(=O)-; X 1 and X 2 One of them is NL 2 -R 2 and the other is CH2; X 3 is CH2 or -O-CH2-; L 2 is -(CH2) n -, -C(=O)-, -C(=O)NH-, -C(=O)(O)-(CH2) n or -S(=O)2; n is 0, 1, or 2; R 1 are aryl or heteroaryl, and are halogen, haloalkyl, hydroxy, alkyl, alkoxy, haloalkoxy, and —N(R 4 ) optionally substituted with 1 or 2 substituents independently selected from: R 2 is aryl, alkyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl, each of which is selected from the group consisting of alkyl optionally substituted with halogen, haloalkyl, hydroxy, alkenyl, or alkoxy, alkoxy optionally substituted with alkenyl or alkoxy, haloalkoxy, heteroaryl, and —N(R 4 ) optionally substituted with 1 or 2 substituents independently selected from: p is 0, 1 or 2; Each R 3 is independently C 1~4 alkyl, or two R on the same carbon 3forms an oxo, where R 3 teeth,

[0072] [ka] one or more ring carbon atoms of which may be substituted; Each R 4 are independently H or C 1-4 alkyl] or an isotopically labeled analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof.

[0073] In some embodiments, the compound of Formula (I) has the formula (IIa):

[0074] [ka] or an isotopically labeled analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof.

[0075] In some embodiments, the compound of Formula (I) has the formula (IIb):

[0076] [ka] or an isotopically labeled analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof.

[0077] In some embodiments, the compound of Formula (I) has the formula (IIIa):

[0078] [ka] or an isotopically labeled analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof.

[0079] In some embodiments, the compound of Formula (I) has the formula (IIIb):

[0080] [ka] or an isotopically labeled analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof.

[0081] In some embodiments, the compound of Formula (I) has the formula (IIIc):

[0082] [ka] or an isotopically labeled analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof.

[0083] In some embodiments, L 1 -OC 1~4 alkylene, and R 1 is hydroxy, alkyl, alkoxy, haloalkoxy and -N(R 4 )2 is heteroaryl optionally substituted with one or two substituents independently selected from:

[0084] In some embodiments, L 1 -OC 1~4 alkylene, and R 1 is pyridinyl optionally substituted with one or two substituents independently selected from hydroxy, alkyl, alkoxy, and haloalkoxy.

[0085] In some embodiments, L 1 -OC 1~4 alkylene, and R 1 is pyridinyl optionally substituted with methoxy.

[0086] In some embodiments, R 1 teeth,

[0087] [ka] is.

[0088] In some embodiments, -L 1 -R 1 teeth,

[0089] [ka] is.

[0090] In some embodiments, L 2 is -C(=O)-.

[0091] In some embodiments, L 2 Ha-(CH2) n - and n is 0.

[0092] In some embodiments, Z 1 and Z 2 are each independently CH.

[0093] In some embodiments, Z 1 and Z 2 One of them is N and the other is CH.

[0094] In some embodiments, Z 1 is N and Z 2 is CH.

[0095] In some embodiments, Z 2 is N and Z 1 is CH.

[0096] In some embodiments, R 2 is heteroaryl.

[0097] In some embodiments, R 2 is a 6-membered heteroaryl ring containing one or two N.

[0098] In some embodiments, R 2 teeth,

[0099] [ka] each of which is selected from hydroxy, alkyl optionally substituted with alkoxy, haloalkyl, alkenyl or alkoxy optionally substituted with alkoxy, haloalkoxy, -N(R 4 )2 and heteroaryl.

[0100] In some embodiments, R 2 is heterocycloalkyl or heterocycloalkenyl.

[0101] In some embodiments, R 2 teeth,

[0102] [ka] each of which is selected from hydroxy, alkyl optionally substituted with alkoxy, haloalkyl, alkenyl or alkoxy optionally substituted with alkoxy, haloalkoxy, -N(R 4 )2 and heteroaryl.

[0103] In some embodiments, Z 3 is CH.

[0104] In some embodiments, X 3 is CH2.

[0105] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0106] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0107] In some embodiments of Formula (I), X 1 and X 2 One of them is NL 2 -R 2 and the other is CH2, CHR 3 or C(R 3 In some embodiments of Formula (I), X 1 and X 2 One of them is NL 2 -R 2 and the other is CH. In some embodiments of Formula (I), X 1 and X 2 One of them is NL 2 -R 2 and the other is CHR 3 In some embodiments of Formula (I), X 1 and X 2 One of them is NL 2 -R 2 and the other is C(R 3 In some embodiments of Formula (I), X 3 is CH2, C(R 3 )2 or CHR 3 is.

[0108] In some embodiments, a compound selected from the compounds of Table 1 or an isotopically labeled analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof is provided.

[0109] In some embodiments, there is provided a compound according to any one of the preceding claims, wherein the compound is labeled with one or more positron-emitting radionuclides.

[0110] In some embodiments, imaging agents are provided that comprise a compound described herein or an isotopically labeled analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof. Also provided are imaging agents that comprise a compound described herein, wherein the compound is labeled with one or more positron-emitting radionuclides.

[0111] In some embodiments, 11 C. 13 N, 15 O and 18 Compounds described herein are provided that contain one or more positron-emitting radionuclides selected from F.

[0112] In some embodiments, there is provided a method of producing a diagnostic image in an individual comprising administering to the individual an effective amount of a compound or imaging agent described herein and producing an image of a body part or body region of the individual.

[0113] In some embodiments, generating an image of a body part or region of an individual includes generating an image to detect the presence or absence of huntingtin protein (HTT protein) in the image; and detecting the presence or absence of a pathological process.

[0114] In some embodiments, the HTT protein is found in the basal ganglia.

[0115] In some embodiments, the pathological process is a neurodegenerative disease.

[0116] In some embodiments, the neurodegenerative disease is selected from Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, prion diseases, and spinocerebellar ataxias.

[0117] In some embodiments, the neurodegenerative disease is Huntington's disease (HD).

[0118] In some embodiments, an effective amount of a compound or imaging agent described herein comprises about 0.1 to about 20 mCi.

[0119] In some embodiments, an effective amount of a compound or imaging agent described herein comprises about 10 mCi.

[0120] In some embodiments, generating the image comprises positron emission tomography (PET) imaging, PET with simultaneous computed tomography imaging (PET / CT), PET with simultaneous magnetic resonance imaging (PET / MRI), single photon emission computed tomography (SPECT) imaging, or a combination thereof.

[0121] In some embodiments, generating an image includes PET imaging.

[0122] In some embodiments, the HTT protein exists as a monomer, oligomer, or aggregate, or a combination thereof. In some embodiments, the HTT protein exists as an aggregate.

[0123] In some embodiments, the HTT protein is a mutant.

[0124] In some embodiments, the body part or region is selected from the head, spine, limbs, chest, or abdomen.

[0125] In some embodiments, the body part or body region is the brain.

[0126] In some embodiments, the compounds described herein may be labeled with one or more positron-emitting radionuclides. In some embodiments, the compounds described herein comprise one or more constituent atoms replaced with a positron-emitting radionuclide, and each positron-emitting radionuclide is an isotope of the atom replaced. Suitable positron-emitting radionuclides that can be incorporated into the compounds described herein include: 11 C. 13 N,15 O. 18 F, 52 Fe, 62 Cu, 64 Cu, 68 Ga, 74 As, 82 Rb, 89 Zr, 122 I and 124 In some embodiments, the one or more positron-emitting radionuclides include, but are not limited to, I. 11 C. 13 N, 15 O. 18 F, 76 Br and 124 I. In some embodiments, the one or more positron-emitting radionuclides are selected from: 11 C. 13 N, 15 O and 18 Selected from F.

[0127] Non-metallic radionuclides can be covalently bound to the compounds described herein by reactions known in the state of the art. It is understood that if the radionuclide is a metallic positron emitter, labeling may require the use of a chelating agent. Such chelating agents are well known in the state of the art.

[0128] In some embodiments, a compound selected from the compounds described in the Examples section is provided. In some embodiments, a compound selected from Table 1 or an isotopically labeled analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof is provided. In some embodiments, a compound of Table 1 labeled with one or more positron-emitting radionuclides is provided.

[0129] [Table 2] TIFF0007720847000018.tif211157TIFF0007720847000019.tif216152TIFF0007720847000020.tif187160TIFF000 7720847000021.tif239156TIFF0007720847000022.tif229154JPEG0007720847000023.jpg233132TIFF00077208470 00024.tif244159TIFF0007720847000025.tif233157TIFF0007720847000026.tif236157JPEG0007720847000027.j pg247152TIFF0007720847000028.tif232149TIFF0007720847000029.tif221144TIFF0007720847000030.tif207150

[0130] In some embodiments, a pharmaceutical composition is provided comprising a compound described herein and a pharmaceutically acceptable carrier.

[0131] Diagnostic Methods and Uses The compounds disclosed herein are useful for detecting conditions or disorders mediated at least in part by proteins prone to protein aggregation. Also provided are methods for generating diagnostic images, such as positron emission tomography (PET) images, in an individual, comprising administering an effective amount of a compound described herein or an imaging agent comprising a compound described herein, and generating an image of a body part or body region of the individual. In some embodiments, the compounds described herein are useful for detecting the presence or absence of huntingtin protein (HTT protein) or its aggregates in diagnostic images.

[0132] Also provided are methods for generating a diagnostic image in a biological sample, comprising contacting the biological sample with an effective amount of a compound or imaging agent described herein and generating an image associated with the biological sample. In some embodiments, the contacting and generating may be performed in vitro. In some embodiments, the contacting is in vivo and the generating is in vitro.

[0133] Also provided are methods for detecting the presence or absence of a pathological process associated with a protein prone to protein aggregation, such as huntingtin protein (HTT protein), in an individual, the methods comprising administering an effective amount of a compound or imaging agent described herein; generating an image to detect the presence or absence of huntingtin protein (HTT protein) in the image; and detecting the presence or absence of the pathological process. In some embodiments, the HTT protein is present as a monomer, oligomer, or aggregate, or a combination thereof. In some embodiments, the huntingtin protein is present as an aggregate thereof. In some embodiments, the individual has or is found to have Huntington's disease. Also provided are methods for detecting the presence or absence of a pathological process associated with β-amyloid protein in an individual, the methods comprising administering an effective amount of a compound or imaging agent described herein; generating an image of a body part or body region of the individual; and detecting the presence or absence of the pathological process. In some embodiments, the individual has or is found to have Alzheimer's disease (AD). In some embodiments, the neurodegenerative disease is selected from Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, prion diseases, and spinocerebellar ataxias.

[0134] In some embodiments, the body part or body region is selected from the head, spinal cord, limbs, chest, and / or abdomen. In some embodiments, the body part or body region is the brain. In some embodiments, the HTT protein is found in the basal ganglia. In some embodiments, the HTT protein is present in the brain, liver, heart, and / or muscle of the individual. In some embodiments, generating an image comprises positron emission tomography (PET) imaging, PET with simultaneous computed tomography imaging (PET / CT), PET with simultaneous magnetic resonance imaging (PET / MRI), single photon emission computed tomography (SPECT) imaging, or a combination thereof. In some embodiments, generating an image comprises PET imaging. In some embodiments, the HTT protein is present in the basal ganglia, cortex, hippocampus, and / or brainstem of the individual's brain. In some embodiments, the HTT protein is present as a monomer, oligomer, or aggregate, or a combination thereof. In some embodiments, the huntingtin protein is present as an aggregate thereof.

[0135] Also provided are diagnostic methods using the compounds or imaging agents described herein to monitor disease progression in a patient by quantifying changes in the levels of aggregation-prone proteins in the patient.

[0136] Methods for producing diagnostic images using positron emission tomography (PET) are provided. PET imaging may be performed as known to those skilled in the art or as follows. PET imaging may involve administering a positron-emitting radionuclide tracer, such as a compound or imaging agent described herein, to an individual. The tracer is allowed sufficient time to bind to a protein of interest when the individual is placed in a scanning device equipped with a ring of scintillation detectors. The emitted positron travels a short (isotope-dependent) distance within the individual's tissues until it interacts with an electron. This interaction annihilates both the electron and the positron, generating a pair of photons. The photons are detected by a scintillator in the scanning device. Non-paired photons are ignored.

[0137] Also provided are methods of producing diagnostic images, including PET with simultaneous computed tomography imaging (PET / CT), PET with simultaneous magnetic resonance imaging (PET / MRI), or single photon emission computed tomography (SPECT) imaging. Generally, computed tomography uses x-rays or gamma rays to detect brain structures, while magnetic resonance imaging uses magnetic fields and radio waves.

[0138] In some embodiments, compounds are provided that have binding rates for HTT or β-amyloid protein aggregates suitable for functioning as imaging agents. Accordingly, the compounds described herein may be characterized by one or more of: 1) high affinity for such protein aggregates; 2) low affinity for adjacent structures; and / or 3) slow dissociation rates from such protein aggregates. The dissociation rate can be calculated by the following formula: assn is the association rate constant) diss It can be expressed as: d[AB] / dt = k assn [A][B] - k diss [AB]

[0139] In some embodiments, an effective amount of a compound or imaging agent described herein comprises about 0.1 to about 20 mCi. In some embodiments, an effective amount of a compound or imaging agent described herein comprises about 0.1, about 0.3, about 0.5, about 0.7, about 1, about 3, about 5, about 7, about 10, about 15, or about 20 mCi. In some embodiments, an effective amount of a compound or imaging agent described herein comprises about 10 mCi.

[0140] Suitable radionuclides that may be incorporated into the compounds described herein include: 3 H (also written as T), 11 C. 18 F, 35 S,123 I, 125 I, 75 Br, 76 Br, 77 Br, 82 Br, 131 I, 15 O. 13 N and 211 Radionuclides that are incorporated into the compound depend on the particular imaging application. In some embodiments, including PET imaging, 11 C. 18 F, 123 I, 131 I, 75 Br, 76 Br or 77 Compounds incorporating a radionuclide selected from Br may be used. 99m Incorporation of chelated radionuclides, such as Tc, may also be useful. 18 The longer half-life of F allows imaging to be performed for a long enough time for a stronger signal to develop. 18 F 11 C. In some embodiments, the compounds or imaging agents described herein may be labeled with a positron-emitting radionuclide or a gamma-emitting radionuclide. Some examples of positron-emitting radionuclides include: 15 O. 13 N, 11 C. 18 F, 76 Br and 124 I, which have half-lives of approximately 2, 10, 20, 110 minutes, 16 hours, and 4.2 days, respectively.

[0141] In some embodiments, the compounds or imaging agents described herein are 11 C and 18 The molecule may be labeled with a positron emitter selected from F. 11 The method for introducing C is 11 C] iodomethane or [ 11Carbon-11 has a half-life of about 20 minutes, and therefore, 11 C must be produced in an on-site cyclotron and, in general, 11 C] produced as carbon dioxide. 11 [C] carbon dioxide is a suitable species for direct labeling (generally [ 11 The radiopharmaceutical is converted to [C]iodomethane, etc., and the synthesis of the radiopharmaceutical is completed on-site for use in PET imaging studies after the appropriate radiochemical purity and specific activity have been determined. 18 A typical way to introduce F is to 18 F] tetrabutylammonium fluoride or [ 18 [F] Potassium fluoride Kryptofix-222 can be used to displace halides, tosylates, or other leaving groups. Fluorine-18 has a half-life of approximately 110 minutes, and thus [ 18 The synthesis of [F] radiopharmaceuticals does not necessarily have to be performed at a cyclotron site or near a PET imaging research center. General methods for the introduction of these positron emitters are described in the literature (see, e.g., Miller et al., Angewandte Chemie International Edition, Vol. 47 (2008), pp. 8998-9033).

[0142] As will be recognized, the steps of the methods described herein need not be performed a particular number of times or in a particular order. Additional objects, advantages, and novel features of the present invention will become apparent to those skilled in the art upon examination of the following examples, which are intended to be illustrative and not limiting.

[0143] Application and Treatment Methods The compounds or imaging agents described herein may be useful for detecting conditions or disorders mediated at least in part by aggregation-prone proteins. In some embodiments, the compounds or imaging agents described herein may be useful for detecting conditions or disorders mediated at least in part by HTT. In some embodiments, treatment of a condition or disorder mediated at least in part by an aggregation-prone protein may include administration of a compound or imaging agent described herein. Treatment may include co-administration of a compound or imaging agent described herein with one or more other therapeutic and / or therapeutic agents.

[0144] In some embodiments, provided are methods of treating or preventing a condition or disorder mediated at least in part by an aggregation-prone protein in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound or imaging agent described herein.

[0145] Exemplary conditions or disorders are listed below.

[0146] Huntington's disease (HD) Huntington's disease (HD) is a hereditary, progressive neurodegenerative disorder characterized by motor, cognitive, and psychiatric impairments, as well as neurodegeneration and brain atrophy. Atrophy begins in the striatum and cortex and spreads to other subcortical brain regions. HD belongs to a group of neurodegenerative disorders in which expanded CAG repeats result in long stretches of polyglutamine (polyQ) in the encoded protein. This group also includes dentatorubral-pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and spinocerebellar ataxias (SCAs). In HD, selective neurodegeneration of gamma-aminobutyric acid-releasing spiny-projection neurons in the striatum has been observed, but neuronal loss in many other brain regions has also been reported. Symptoms of HD include loss of motor control, psychiatric symptoms, and memory and / or cognitive impairment.

[0147] The HD protein huntingtin (HTT protein) is a 348 kDa multidomain protein containing a polymorphic glutamine / proline-rich domain at its amino terminus. 15 The number of CAG repeats in the gene varies from 6 to 35 in healthy individuals, with 36 or more repeats defining the HD allele. 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. Longer polyQ domains are thought to cause conformational changes in the HTT protein, leading to the formation of intracellular aggregates that often appear as nuclear inclusions. However, aggregates can also form outside the nucleus. The HTT protein is present in the nucleus, cell body, dendrites, and nerve terminals of neurons and is also associated with many organelles, including the Golgi apparatus, endoplasmic reticulum, and mitochondria.

[0148] The part of the brain most affected by HD, and therefore most likely to contain HTT protein abnormalities, is a group of nerve cells at the base of the brain collectively known as the basal ganglia. The basal ganglia organize muscle-propelled body movements, or "motor activity." The main components of the basal ganglia are the caudate nucleus and putamen (together known as the striatum) and the globus pallidus (external and internal regions). The substantia nigra and subthalamic nucleus are often included as part of the basal ganglia as well.

[0149] The basal ganglia are a group of subcortical nuclei primarily responsible for motor control, as well as other roles such as motor learning, executive function, behavior, and emotion. Disruption of the basal ganglia network is thought to lead to several movement disorders. Normal function of the basal ganglia requires fine-tuning of neuronal excitability within each nucleus to determine the degree of motor facilitation or inhibition at any given time. This is mediated by the complex organization of the striatum, where the excitability of medium spiny neurons is controlled by several pre- and post-synaptic mechanisms and interneuron activity, and ensured by several recurrent or internal basal ganglia circuits. The basal ganglia motor circuit has two input points, the striatum and subthalamic nucleus, and one output point, the internal pallidal segment, which connects to the cortex via the motor thalamus.

[0150] Methods for generating an image of a body part or region of an individual are provided, which involve administering to the individual a compound or imaging agent described herein. In some embodiments, the compound or imaging agent is administered to the individual's vasculature. The compound or imaging agent is capable of crossing the blood-brain barrier. Thus, generating an image can include generating an image of at least a portion of the individual's brain, e.g., a portion into which the compound is distributed.

[0151] In some embodiments, the pathological process is a condition or disorder selected from Huntington's disease (HD), dentatorubral-pallidoluysian atrophy, spinal-bulbar muscular atrophy, spinocerebellar degeneration, spinal cord and / or brain injury, chronic pulmonary hypertension, Parkinson's disease, amyotrophic lateral sclerosis, cerebral cavernous hemangioma, cardiovascular disease, Alzheimer's disease (AD), glaucoma, multiple sclerosis (MS), corneal lesions, diabetes, chronic and / or neuropathic pain, stroke, ischemia, retinal disease, spinal muscular atrophy (SMA), erectile dysfunction, (non-hypertensive) nephropathy, hypertensive nephropathy, high blood pressure (hypertension), optic nerve damage, liver fibrosis, lupus, post-transplant liver failure, encephalomyelitis, epilepsy, and glioblastoma. In some embodiments, the pathological process is a neurodegenerative disease selected from Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, prion diseases, and spinocerebellar ataxias. In some embodiments, the neurodegenerative disease is classified as a triplet repeat disease. In some embodiments, the triplet repeat disease is classified as belonging to Category I, Category II, or Category III.

[0152] In some embodiments, the neurodegenerative disease is Huntington's disease.

[0153] Imaging agents and their administration Imaging agents generally include compounds described herein labeled with a positron-emitting radionuclide. Positron-emitting radionuclide-labeled imaging agents are generally administered via intravenous injection within one hour of synthesis due to the short half-life of the radionuclide. The amount of imaging agent required is typically determined by the prescribing physician. Dosages may vary depending on the amount of emission from the radionuclide used. Those skilled in the art will appreciate that an effective amount would be an amount of compound sufficient to produce an emission in the range of about 0.1 to about 20 mCi, or about 1 to about 5 mCi. The amount of labeled compound in an effective amount of imaging agent may be about 0.1 to about 500 mg.

[0154] The following example illustrates an exemplary, non-limiting procedure that may be utilized when conducting a PET imaging study on an individual in a clinical setting. The individual may be naive or previously medicated with an unlabeled compound. The individual may be allowed free access to water and may have fasted for at least 12 hours. A 20G, 2-inch intravenous catheter may be inserted into the contralateral ulnar vein for administration of the imaging agent.

[0155] A human subject is placed in the PET camera and a tracer dose of imaging agent is administered via an intravenous catheter. Arterial or venous blood samples are obtained at appropriate time intervals during the PET scan to analyze and quantify the fraction of unmetabolized compound in the plasma. Images are acquired over a maximum period of 120 minutes. Within 10 minutes of the injection of the radiotracer, and at the end of the imaging session, 1 ml blood samples are obtained to determine the plasma concentration of any unlabeled imaging agent (or other interventional compound) that may have been administered prior to the PET tracer.

[0156] Tomographic images can also be obtained by image reconstruction. Regions of interest (ROIs) can be established on the reconstructed images to determine, for example, the distribution of the imaging agent. Regions of interest in brain images can include, for example, the striatum, cerebellum, or basal ganglia. The amount of imaging agent absorbed over time in these regions can be used to generate time-activity curves (TACs). The data can be expressed as radioactivity per unit time per unit volume (e.g., μCi / cc / mCi injected dose) or radioactivity per unit volume. TAC data can be processed by various methods known in the art to obtain quantitative parameters, such as binding potential (BP).

[0157] In general, the compounds or imaging agents described herein can be administered to a patient in need thereof via any suitable route. Routes of administration can include parenteral administration, such as subcutaneous, intramuscular, or intravenous, for example, via a drip patch. Further suitable routes of administration include, but are not limited to, oral, rectal, intranasal, topical (including buccal and sublingual), injection, vaginal, intradermal, intraperitoneal, intracranial, intrathecal, and epidural administration, for example, via a spray or inhaler, or via an implant, or via oral or nasal inhalation.

[0158] For PET imaging, administration of the compounds or imaging agents described herein to an individual may be intravenous. Pharmaceutical compositions may take the form of a sterile injectable aqueous or oily suspension. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents, as listed above. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable vehicles, such as solutions in 1,3-butanediol. Among the acceptable vehicles that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating, fixed oil may be used, including synthetic mono- and diglycerides. Additionally, fatty acids, such as oleic acid, may be useful in the preparation of injectables. Such solutions may be formulated as 0.01% to 10% isotonic solutions, pH 5 to 7, and appropriate salts.

[0159] The compounds or imaging agents described herein may be administered parenterally in a sterile medium. Parenteral administration includes subcutaneous injection, intravenous, intramuscular, intrathecal injection, or infusion techniques. The compounds or imaging agents described herein may be suspended or dissolved in a vehicle, depending on the vehicle and concentration used. Advantageously, adjuvants such as local anesthetics, preservatives, and buffering agents can be dissolved in the vehicle. In many pharmaceutical compositions for parenteral administration, the carrier accounts for at least 90% by weight of the total composition. In some embodiments, the carrier for parenteral administration is selected from propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil.

[0160] The compounds or imaging agents described herein may be administered via microspheres, liposomes, other microparticulate delivery systems, or sustained-release formulations placed in specific tissues, including blood. Suitable examples of sustained-release carriers include semipermeable polymer matrices in the form of co-medical products, such as suppositories or microcapsules. Examples of the above techniques or protocols and other techniques or protocols that can be used in accordance with the present invention can be found in Remington's Pharmaceutical Sciences, 18th Edition, Gennaro, AR, Lippincott Williams & Wilkins; 20th Edition (December 15, 2000) ISBN 0-912734-04-3 and Pharmaceutical Dosage Forms and Drug Delivery Systems, Ansel, NC et al., 7th Edition, ISBN 0-683305-72-7, the entire contents of which are incorporated herein by reference.

[0161] The dosage of the compounds or imaging agents described herein will depend on a variety of factors, including the particular pathological process being treated or detected, the physiology of the individual, the severity of the symptoms, the route of administration, the frequency of dosing intervals, the particular compound utilized, the efficacy of the compound, the toxicological profile, the pharmacokinetic profile, and the presence of toxic side effects, and other considerations. The dosage for a particular situation will be determined appropriately by the practitioner based on these and other factors.

[0162] The compounds or imaging agents described herein are typically administered at dosage levels determined by a practitioner, such as a physician. For example, the compounds or imaging agents are generally administered at dosage levels of 0.001-100 mg / kg, e.g., 0.01-100 mg / kg, e.g., 0.1-70 mg / kg, e.g., 0.5-10 mg / kg, in single or multiple doses. Dosages may be, for example, once daily or twice daily. A unit dosage form may generally contain 0.01-1000 mg, e.g., 0.1-50 mg, of a compound or imaging agent described herein. For intravenous administration, the compounds or imaging agents may be administered at dosage levels of, for example, 0.001-50 mg / kg, e.g., 0.001-10 mg / kg, e.g., 0.01-1 mg / kg, in single or multiple doses. A unit dosage form may contain, for example, 0.1 to 10 mg of compound or imaging agent.

[0163] In some embodiments, the compounds or imaging agents described herein are administered as pharmaceutical compositions.Therefore, pharmaceutical compositions are provided that include at least one compound or imaging agent described herein, together with at least one pharmaceutically acceptable vehicle selected from carriers, adjuvants, and excipients.The compounds or imaging agents of the present invention can be formulated into pharmaceutical compositions using techniques known to those skilled in the art.

[0164] Pharmaceutically acceptable vehicles must be of sufficiently high purity and sufficiently low toxicity to make them suitable for administration to the animal being treated. The vehicle can be inert, or it can have a pharmaceutical benefit. The amount of vehicle used with the compound or imaging agent can be sufficient to provide a practical amount of material for administration per dose of compound or imaging agent.

[0165] Exemplary pharmaceutically acceptable carriers or components thereof are sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and methylcellulose; powdered tragacanth; malt; gelatin; talc; solid lubricating oils such as stearic acid and magnesium stearate; calcium sulfate; synthetic oils; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, and corn oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; phosphate buffer solutions; emulsifiers such as TWEEN®; wetting agents such as sodium lauryl sulfate; colorants; flavorings; tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0166] Optional active agents may be included in the pharmaceutical compositions, which do not substantially interfere with the activity of the compounds or imaging agents described herein.

[0167] At least one compound or imaging agent described herein at an effective concentration is mixed with a suitable pharmaceutically acceptable vehicle.If the compound or imaging agent shows insufficient solubility, a method for solubilizing the compound may be used.Such methods are known to those skilled in the art and include, but are not limited to, using a cosolvent such as dimethyl sulfoxide (DMSO), using a surfactant such as TWEEN®, or dissolving in an aqueous buffer solution, such as sodium bicarbonate.

[0168] Upon mixing or addition of a compound or imaging agent described herein, the resulting mixture may be a solution, suspension, emulsion, etc. The form of the resulting mixture will depend on many factors, including the intended method of administration and the solubility of the compound or imaging agent in the selected vehicle. Effective concentrations sufficient for imaging or treatment can be determined empirically by methods known in the art.

[0169] Pharmaceutical compositions may be formulated for oral use, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Pharmaceutical compositions intended for oral use may be prepared according to any method known to those skilled in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, such as sweeteners, flavoring agents, coloring agents, and preservatives, to provide a pharmaceutically simple and palatable product. In some embodiments, oral pharmaceutical compositions contain 0.1-99% of a compound or imaging agent described herein. In some embodiments, oral pharmaceutical compositions contain at least 5% (by weight) of a compound or imaging agent. Some embodiments contain 25%-50% or 5%-75% of a compound or imaging agent.

[0170] Orally administered pharmaceutical compositions also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups, etc. Pharmaceutically acceptable carriers suitable for preparing such compositions are well known in the art. Oral pharmaceutical compositions may also contain preservatives, flavoring agents, sweeteners such as sucrose or saccharin, taste-masking agents, and coloring agents.

[0171] Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. Syrups and elixirs may be formulated with sweeteners, such as glycerol, propylene glycol, sorbitol or sucrose. Such pharmaceutical compositions may also contain a demulcent.

[0172] The compounds or imaging agents described herein can be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs. Additionally, pharmaceutical compositions containing the compounds or imaging agents described herein can be presented as a dry product for constitution with water or another suitable vehicle before use. Such liquid preparations can contain conventional additives, such as suspending agents (e.g., sorbitol syrup, methylcellulose, glucose / sugar, syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, and hydrogenated edible fats), emulsifiers (e.g., lecithin, sorbitan monooleate, or acacia), non-aqueous vehicles, such as edible oils (e.g., almond oil, fractionated coconut oil, silyl esters, propylene glycol, and ethyl alcohol), and preservatives (e.g., methyl or propyl p-hydroxybenzoates and sorbic acid).

[0173] For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, Avicel® RC-591, tragacanth, and sodium alginate, typical wetting agents include lecithin and polysorbate 80, and typical preservatives include methylparaben and sodium benzoate.

[0174] Aqueous suspensions are provided containing the compound or imaging agent in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia. Dispersing or wetting agents can be naturally occurring phosphatides, such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitols, such as substituted polyethylene sorbitols, or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitol anhydrides, such as substituted polyethylene sorbitan. Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate.

[0175] Oily suspensions can be formulated by suspending the compound or imaging agent in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil, such as liquid paraffin. Oily suspensions can contain thickening agents, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners, such as those identified above, and flavoring agents can be added to provide a palatable oral product. These pharmaceutical compositions can be preserved by adding an antioxidant, such as ascorbic acid.

[0176] The pharmaceutical composition may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring gums, such as gum acacia or gum tragacanth, naturally occurring phosphatides, such as soybean, lecithin, and esters or partial esters derived from fatty acids and hexitols, anhydrides, such as sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, such as polyethylene sorbitan monooleate.

[0177] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.

[0178] Tablets typically contain conventional pharmaceutically acceptable adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose; binders such as starch, gelatin, and sucrose; disintegrants such as starch, alginic acid, and croscarmellose; and lubricants such as magnesium stearate, stearic acid, and talc. Lubricants such as silicon dioxide can be used to improve the flow properties of the powder mixture. Coloring agents, such as FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, can be useful adjuvants for chewable tablets. Capsules (including time-release and sustained-release formulations) typically contain one or more solid diluents as disclosed above. The selection of carrier components is often based on secondary considerations such as taste, cost, and storage stability.

[0179] The pharmaceutical compositions may be coated by conventional methods, typically with pH or time dependent coatings, so that the compound or imaging agent is released in the gastrointestinal tract in the vicinity of the desired local application or at various times to prolong the desired effect. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, ethylcellulose, Eudragit® coatings, waxes, and shellac.

[0180] Pharmaceutical compositions for oral use may also be presented as hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules, in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

[0181] The compounds or imaging agents described herein may be administered in the form of suppositories for rectal administration of the drug. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol.

[0182] The compounds or imaging agents described herein may be formulated for local or topical application, for example, for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams and lotions, and for application to the eye. Topical pharmaceutical compositions may be in any form, including, for example, solutions, creams, ointments, gels, lotions, emulsions, cleansers, moisturizers, sprays, skin patches, etc.

[0183] Topical pharmaceutical compositions comprising at least one compound described herein or an isotopically labeled analogue, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof can be mixed with a variety of carrier materials known in the art, such as water, alcohol, aloe vera gel, allantoin, glycerin, vitamin A and E oil, mineral oil, propylene glycol, PPG-2 myristyl propionate, and the like.

[0184] Other materials suitable for use in topical carriers include, for example, emollients, solvents, humectants, thickeners, and powders. Examples of each of these types of materials, which may be used alone or in mixtures with one or more other materials, are as follows:

[0185] Representative emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecane-2-ol, isocetyl alcohol, cetyl palmitate, and dimethylpolysiloxane. , di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, peanut oil, castor oil, acetylated lanolin alcohol, petroleum oil, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate and myristyl myristate; propellants such as propane, porcine solvents such as ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran; humectants such as glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, and gelatin; and powders such as chalk, talc, fuller's earth, kaolin, starch, gum, colloidal silicon dioxide, sodium polyacrylate, tetraalkylammonium smectite, trialkylarylammonium smectite, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose, and ethylene glycol monostearate.

[0186] The compounds or imaging agents described herein may also be formulated for transdermal administration as a transdermal patch.

[0187] The compounds or imaging agents described herein may also be administered in a liposome delivery system. Liposomes can be classified into small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of amphiphilic molecules, particularly phospholipids. Liposome components include cholesterol, stearylamine, and / or phosphatidylcholine. Liposomes are suitable for various routes of administration, including topical administration and injection into various tissues. Thus, intravitreal (e.g., in the treatment of glaucoma), intraperitoneal, intravenous, intravascular, intraarticular, and intramuscular administration of liposomes are contemplated.

[0188] Other pharmaceutical compositions useful for achieving systemic delivery of compounds or imaging agents include sublingual, buccal, and nasal dosage forms. Such pharmaceutical compositions typically contain soluble filler substances such as sucrose, sorbitol, and mannitol, and one or more binders such as acacia, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose. The glidants, lubricants, sweeteners, colorants, antioxidants, and flavoring agents disclosed above may also be included.

[0189] Pharmaceutical compositions for inhalation can typically be provided in the form of a solution, suspension or emulsion, which can be administered as a dry powder or in the form of an aerosol using conventional propellants (e.g., dichlorodifluoromethane or trichlorofluoromethane).

[0190] The pharmaceutical compositions may optionally include an activity enhancer. Activity enhancers can be selected from a wide variety of molecules that function in a variety of ways that enhance or are independent of the therapeutic effect of the compounds or imaging agents described herein. Particular classes of activity enhancers include skin penetration enhancers and absorption enhancers.

[0191] The pharmaceutical compositions may contain additional active agents, which may be selected from a wide variety of molecules that function in various ways to enhance the therapeutic effect of the compounds or imaging agents described herein. When present, these optional other active agents are typically utilized in the pharmaceutical composition at levels ranging from 0.01% to 15%. In some embodiments, they comprise 0.1% to 10% by weight of the composition. In other embodiments, they comprise 0.5% to 5% by weight of the composition.

[0192] Packaging Packaged pharmaceutical compositions are also provided. Such packaged compositions include a pharmaceutical composition containing a compound or imaging agent described herein and instructions for using the composition to treat a subject (typically a human patient). In some embodiments, the instructions are for using the pharmaceutical composition to detect a condition or disorder described herein. The packaged pharmaceutical composition may include prescribing information, for example, to the patient or healthcare provider, or as a label on the packaged pharmaceutical composition. The prescribing information may include, for example, efficacy, dosage and administration, contraindications, and adverse reaction information for the pharmaceutical composition.

[0193] In all of the foregoing, the compounds or imaging agents may be administered alone, as mixtures, or in combination with other active agents.

[0194] Combination treatment The methods described herein include methods for detecting, treating, or preventing a condition or disorder described herein, e.g., Huntington's disease, comprising administering to a subject a compound or imaging agent described herein and one or more additional agents simultaneously or sequentially. In methods using simultaneous administration, the agents may be present in a combined composition or may be administered separately. When used in combination with one or more additional pharmaceutical agents, a compound or imaging agent described herein may be administered before, simultaneously with, or after administration of the additional active agent.

[0195] Pharmaceutical compositions are also provided that include a compound or imaging agent described herein and one or more additional pharmaceutical agents used in the treatment of Huntington's disease, such as, but not limited to, carbamazepine, clonazepam, diazepam, fluoxetine, escitalopram, valproate, lamotrigine, amitriptyline, imipramine, desipramine, nortriptyline, paroxetine, fluoxetine, sertraline, tetrabenazine, haloperidol, chlorpromazine, thioridazine, sulpiride, quetiapine, clozapine, and risperidone. Also provided are packaged pharmaceutical compositions comprising a pharmaceutical composition comprising a compound or imaging agent described herein and another composition comprising one or more pharmaceutical agents used to treat Huntington's disease, such as, but not limited to, carbamazepine, clonazepam, diazepam, fluoxetine, escitalopram, valproate, lamotrigine, amitriptyline, imipramine, desipramine, nortriptyline, paroxetine, fluoxetine, sertraline, tetrabenazine, haloperidol, chlorpromazine, thioridazine, sulpiride, quetiapine, clozapine, and risperidone. In some embodiments, the active agent is carbamazepine, clonazepam, diazepam, fluoxetine, escitalopram, valproate, lamotrigine, amitriptyline, imipramine, desipramine, nortriptyline, paroxetine, fluoxetine, sertraline, tetrabenazine, haloperidol, chlorpromazine, thioridazine, sulpiride, quetiapine, clozapine, or risperidone.

[0196] Also provided are methods for treating or preventing Alzheimer's disease, including memory and / or cognitive impairment associated with Alzheimer's disease, comprising administering to a subject, simultaneously or sequentially, a compound or imaging agent described herein and one or more additional agents. In some embodiments, the active agent is Reminyl®, Cognex®, Aricept®, Exelon®, Akatinol®, Neotropin™, Eldepryl®, estrogen, or clioquinol.

[0197] Also provided is the use of a compound or imaging agent described herein for the manufacture of a medicament for use in the diagnosis, prevention, or treatment of a condition or disorder described herein.

[0198] Compound synthesis The compounds described herein can be prepared using the methods disclosed herein and routine variations thereof that are apparent from the disclosures 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. Where available, reagents can be purchased commercially, for example, from Sigma Aldrich or other chemical suppliers.

[0199] The compounds described herein can be prepared, for example, from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, it is understood that other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the specific reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0200] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in Wuts, PGM, Greene, TW, & Greene, TW (2006). Greene's protective groups in organic synthesis. Hoboken, NJ, Wiley-Interscience and the references cited therein.

[0201] Additionally, the compounds described herein may contain one or more asymmetric ("chiral") centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are within the scope of the present invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, supercritical fluid chromatography, chiral resolving agents, and the like.

[0202] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chem or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures or obvious modifications thereof described in standard reference works such as Fieser and Fieser's Reagents for Organic Synthesis, volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, volumes 1-5 and supplements (Elsevier Science Publishers, 1989), Organic Reactions, volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 5th ed., 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0203] The terms "solvent," "inert organic solvent," or "inert solvent" refer to a solvent that is inert under the conditions of the reaction being described therewith (e.g., benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine, and the like). Unless otherwise specified, the solvents used in the reactions of the present invention are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen.

[0204] The term "qs" means adding a quantity sufficient to achieve a stated function, for example, to bring a solution to the desired volume (ie, 100%).

[0205] It is also understood that the addition of any substituent in each of the above schemes may result in the production of multiple isomeric products (including, but not limited to, enantiomers or one or more diastereomers), any or all of which can be isolated and purified using conventional techniques. Where an enantiomerically pure or enriched compound is desired, chiral chromatography and / or enantiomerically pure or enriched starting materials may be utilized as conventionally used in the art or as described in the Examples.

[0206] Incorporation of labels into the compounds or imaging agents described herein may be carried out by reacting a suitable starting material with a reagent containing a radioisotope. [Example]

[0207] The following examples are included to demonstrate specific embodiments of the invention. It should be understood by those skilled in the art that the techniques disclosed in the examples which follow represent fully functional techniques in the practice of the invention and can thereby be considered to constitute specific modes for its implementation. However, in light of the present invention, those skilled in the art should appreciate that numerous changes can be made to the specific embodiments disclosed and still achieve similar results without departing from the spirit and scope of the invention.

[0208] Compounds were named using Cambridgesoft Chemistry Cartridge (v.16.0.0.82) software.

[0209] Analysis method Acid phase HPLC method Analytical HPLC-MS (METCR1673) was performed on a Shimadzu LCMS-2010EV system using a Supelco Ascentis Express reverse-phase column (2.7 μm, 2.1 × 30 mm) with a gradient of 5 to 100% B (A = water / 0.1% formic acid, B = acetonitrile / 0.1% formic acid) at a column temperature of 40 °C for 1.5 min, followed by 100% B for 0.1 min, with an injection volume of 3 μL and a flow rate of 1.0 mL / min. UV spectra were recorded at 215 nm using an SPD-M20A photodiode array (PDA) detector. Mass spectra were acquired over the m / z range of 100 to 1000 using the LCMS2010EV at a sampling rate of two scans per second. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[0210] Alternatively, HPLC-MS (METCR1410) was performed on a Shimadzu LCMS-2010EV system using a Kinetix Core-Shell C18 reverse-phase column (5 μm, 2.1 × 50 mm) with a gradient of 5 to 100% B (A = water / 0.1% formic acid, B = acetonitrile / 0.1% formic acid) at a column temperature of 40°C for 1.2 min, followed by 100% B for 0.1 min, with an injection volume of 3 μL and a flow rate of 1.2 mL / min. All other aspects of the method remained unchanged.

[0211] Alternatively, analytical HPLC-MS (METCR1416) was performed on a Shimadzu LCMS-2010EV system using a Waters Atlantis dC18 reverse-phase column (3 μm, 2.1 × 100 mm) with a gradient of 5–100% B (A = water / 0.1% formic acid, B = acetonitrile / 0.1% formic acid) at 40 °C for 5.0 min, followed by 100% B for 0.4 min, with an injection volume of 3 μL and a flow rate of 0.6 mL / min. UV spectra were recorded at 215 nm using an SPD-M20A PDA detector. Mass spectra were acquired over the m / z range of 100–1000 using the LCMS2010EV at a sampling rate of two scans per second. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[0212] Alternatively, analytical HPLC-MS (MET-uHPLC-AB-101) was performed on a Waters Acquity UPLC system equipped with a Waters PDA and ELS detector, using a Phenomenex Kinetex-XB C-18 column (1.7 μm, 2.1 × 100 mm) with a gradient of 5 to 100% B (A = water / 0.1% formic acid, B = acetonitrile / 0.1% formic acid) at 40 °C for 5.3 min, followed by 100% B for 0.5 min at a flow rate of 0.6 mL / min. UV spectra were recorded at 215 nm using a Waters Acquity PDA detector. Mass spectra were acquired over the m / z range of 150 to 850 using a Waters ZQ detector, sampling at a rate of two scans per second. OpenLynx software was used to integrate data and generate reports.

[0213] Alternatively, mass spectra and LCMS analyses were obtained using a Waters Acquity SQD (ESI, UP-LCMS) (MET-AMRI001). HPLC analyses were obtained on an XBridge C18 column, 3.5 μm (4.6 × 150 mm), eluted according to solvent gradient method 1. Detection was by UV at 254 and 215 nm.

[0214] Method 1

[0215] [Table 3]

[0216] Basic Phase HPLC Method Analytical HPLC-MS (METCR0990) was performed on a Hewlett Packard HPLC system using a Phenomenex Gemini C18 reverse-phase column (3 μm, 2.0 × 50 mm) with a gradient of 1 to 100% B (A = 2 mM ammonium bicarbonate in water buffered to pH 10, B = acetonitrile) at a column temperature of 60 °C for 1.8 min, followed by 100% B for 0.3 min, with an injection volume of 3 μL and a flow rate of 1 mL / min. UV spectra were recorded at 215 nm using a Waters PDA detector. Mass spectra were acquired over the m / z range of 150 to 850 using a Waters ZQ at a sampling rate of 2 scans per second. OpenLynx software was used to integrate and generate reports.

[0217] Analytical HPLC-MS (METCR1600) was performed on a Hewlett Packard HPLC system using a Phenomenex Gemini C18 reverse-phase column (3 μm, 2.0 × 100 mm) with a gradient of 5 to 100% B (A = 2 mM ammonium bicarbonate in water buffered to pH 10, B = acetonitrile) for 5.5 min, followed by 100% B for 0.4 min, with an injection volume of 3 μL and a flow rate of 0.5 mL / min. UV spectra were recorded at 215 nm using a Waters PDA detector. Mass spectra were acquired over the m / z range of 150 to 850 using a Waters ZQ at a sampling rate of 2 scans per second. OpenLynx software was used to integrate and generate reports.

[0218] The METCR1600 method was then replaced with METCR1603 and the flow rate was increased to 0.6 mL / min, all other parameters remaining unchanged.

[0219] Alternatively, analytical HPLC-MS (MET-uHPLC-AB-102) was performed on a Waters Acquity UPLC system equipped with a Waters PDA and ELS detector, using a Waters UPLC® CSH™ column (1.7 μm, 2.1 × 100 mm) with a gradient of 5 to 100% B (A = 2 mM ammonium bicarbonate in water buffered to pH 10, B = acetonitrile) at a column temperature of 40 °C for 5.3 min, followed by 100% B for 0.5 min, with an injection volume of 1 μL and a flow rate of 0.6 mL / min. UV spectra were recorded at 215 nm using a Waters Acquity PDA detector. Mass spectra were acquired over the m / z range of 150 to 850 using a Waters Quattro Premier XE detector, with a sampling rate of 2 scans per second. OpenLynx software was used to integrate data and generate reports.

[0220] General Experimental Procedure The compounds of the present invention can be synthesized according to the general reaction schemes and / or the examples below. The general schemes can be modified to obtain the corresponding products by replacing the starting materials with other materials having similar structures. From the structure of the desired product, the necessary starting materials will generally be apparent to one skilled in the art.

[0221] Scheme 1 shows an exemplary synthetic route for the synthesis of compounds provided herein (e.g., compounds of Formula I). Compounds of Formula I or other formulas or compounds disclosed herein are typically prepared by first providing a core compound of Formula X(a1) or X(a2), and then attaching the desired substituents using suitable conditions (e.g., coupling, amide bond formation, etc.).

[0222] In some embodiments, the synthesis of compounds of Formula (I) proceeds according to Scheme 1.

[0223] In Scheme 1, a compound of formula X(a1) is converted into a compound of formula X(b1) or X(c1) (X 1 NL 2 -R 2 or the compound of formula X(a2) is converted into a compound of formula X(b2) or X(c2) (X 2 NL 2 -R 2 (corresponding to a compound of formula (I) which is:) Next, a compound of formula X(b1) or X(c1) can be converted to a compound of formula (d1), or a compound of formula X(b2) or X(c2) can be converted to a compound of formula X(d2), respectively. A compound of either formula X(d1) or X(d2) can then be converted to a compound of formula (I). In Scheme 1, L 1 , L 2 , R 1 , R 2 , X 3 , Z 1 , Z 2 , Z 3 and p is as defined in formula (I). Compounds of formula (I) can be obtained by known methods or by methods described herein, particularly those described for the synthesis of any of Methods 1 to 41.

[0224] [ka]

[0225] In Scheme 1, PG 1 and P.G. 2 Each of PG may independently be hydrogen or a suitable nitrogen protecting group, such as a carbamate (e.g., tert-butoxycarbonyl, etc.) or a sulfur derivative (e.g., S(O)CH), or an acyl halide, such as acyl chloride. 1 or PG 2 When PG is a protecting group, the group may be removed under suitable conditions (e.g., with TFA or HCl in the case of Boc). 1 or PG 2 is hydrogen, R 21 or R22 The moiety can be reacted under suitable conditions, such as (sulfon)amide coupling conditions (e.g., R 21 or R 22 is a carboxylic acid, HATU or EDCI and DIPEA, or R 21 or R 22 When PG is an acyl halide or sulfonyl halide, it may be added with a base such as DIPEA. 1 or PG 2 can also undergo substitution under nucleophilic aryl coupling conditions, for example, using a metal catalyst (e.g., Pd(dba)3, RuPhos, Pd(OAc)2) optionally in contact with a ligand (e.g., BINAP, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, CyJohnPhos) in the presence of a base (e.g., Cs2CO3, NaOtBu, KOtBu, NaH, Na2CO3) in an inert solvent (e.g., 1,4-dioxane, DMF, THF). PG 1 or PG 2 can also undergo substitution under nucleophilic conditions with a suitable electrophile (e.g., a primary halide) in the presence of a base (e.g., Cs2CO3) and optionally potassium iodide. 1 or PG 2 is an acyl halide, R 21 or R 22 can be added by nucleophilic displacement of a halide by a nucleophile, such as a secondary amine.

[0226] L 11 and L 12 L may be a hydroxyl, a hydroxyl protected by a hydroxyl protecting group (e.g., benzyl), or a leaving group (e.g., a halide). 11 or L 12 is hydroxyl, R 11 or R 12L can be added by a nucleophilic substitution reaction, such as a nucleophilic halide displacement with an alkyl halide partner (e.g., an alkyl chloride or bromide, a base such as CsCO, and optionally potassium iodide), or a Mitsunobu reaction with a suitable alcohol (e.g., a primary alcohol) partner (e.g., in the presence of CMBP). 11 or L 12 is a leaving group, R 11 or R 12 can be added under nucleophilic aryl coupling conditions using, for example, a metal catalyst (e.g., Pd(dba)3, RuPhos, Pd(OAc)2) optionally in contact with a ligand (e.g., BINAP, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, CyJohnPhos) in an inert solvent (e.g., 1,4-dioxane, DMF, THF) in the presence of a base (e.g., Cs2CO3, NaOtBu, KOtBu, NaH, Na2CO3). 11 or L 12 is an amine, R 11 or R 12 is amide coupling conditions (e.g., R 11 or R 12 If is a carboxylic acid, it can be added under HATU or EDCI, and DIPEA).

[0227] R 11 is R 1 or derivatives thereof, such as hydroxyl derivatives (e.g., R 1 The allylic alcohol or R corresponding to the hydroxyl 1 R may be a hydroxyl corresponding to the methyl ether of 21 is R 2 or derivatives thereof, such as hydroxyl protected derivatives (e.g., R 1 R may be an allyl alcohol corresponding to 11 is a hydroxy group that can be converted to R under conditions known in the art or described herein. 1 or R 21 is R 2 may be converted to

[0228] Commercially available reagents and solvents (HPLC grade) were used without further purification. Chromatography was performed in deuterated solvents on a Bruker DRX 500 MHz spectrometer, a Bruker DPX 250 MHz spectrometer, a Bruker AVANCE 300 spectrometer, or a Bruker AVANCE 500 spectrometer. 1 H NMR spectra were recorded. Chemical shifts (δ) are expressed in parts per million. Flash column chromatography refers to automated purification on a Biotage Isolera system using appropriately sized SNAP or KPNH pre-packed silica columns and solvents as recorded in the experimental section. Thin-layer chromatography (TLC) analysis was performed on Kieselgel 60 F254 (Merck) plates and visualized using UV light. SCX chromatography was performed by loading samples in methanol onto a Biotage Isolute Flash SCX-2 and eluting with methanol followed by 5% ammonia in methanol.

[0229] All exemplified compounds exhibit LC purity >95% unless otherwise stated.

[0230] Method 1 Method 1 scheme

[0231] [ka]

[0232] [Example 1] 7-[(5-methoxypyridin-2-yl)methoxy]-2-(6-methoxypyridine-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline 2-(chloromethyl)-5-methoxypyridine (5-Methoxypyridin-2-yl)methanol (200 mg, 1.37 mmol) was dissolved in DCM (5 mL), thionyl dichloride (198 μL, 2.73 mmol) was added, and the reaction mixture was stirred at room temperature under nitrogen for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was co-evaporated with DCM (3 × 10 mL) and concentrated to dryness to give the title compound. Tr (METCR1410) = 0.82 min, (ES + ) (M+H) + 158 / 160.

[0233] tert-Butyl 7-[(5-methoxypyridin-2-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate 2-(Chloromethyl)-5-methoxypyridine (100 mg, 0.63 mmol), tert-butyl 7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (158 mg, 0.63 mmol), KI (105 mg, 0.63 mmol), and CsCO (419 mg, 1.27 mmol) were dissolved in DMF (5 mL), and the reaction mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with water. Purification by column chromatography (silica, 0-80% EtOAc in heptane) gave the title compound. Tr (METCR1410) = 1.24 min, (ES + ) (M+H) + 371, 94%. 1 H NMR (500 MHz, DMSO-d6) δ 8.27 (d, J = 2.7 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.41 (dd, J = 8.6, 2.8 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.88 - 6.77 (m, 2H), 5.06 (s, 2H), 4.44 (s, 2H), 3.83 (s, 3H), 3.51 (t, J = 5.9 Hz, 2H), 2.68 (t, J = 5.8 Hz, 2H), 1.42 (s, 9H).

[0234] 7-[(5-Methoxypyridin-2-yl)methoxy]-1,2,3,4-tetrahydroisoquinolin-2-ium chloride (Example 1.30) tert-Butyl 7-[(5-methoxypyridin-2-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (120 mg, 0.32 mmol) was suspended in 4N HCl in dioxane (10 mL) and sonicated for 5 minutes. The suspension was stirred at room temperature for 3.5 hours. The resulting material was filtered to give the title compound. Tr (METCR1410) = 0.75 min, (ES + ) (M+H) + 271. 1 H NMR (500 MHz, DMSO-d6) δ 9.34 (s, 2H), 8.35 (dd, J = 2.2, 1.1 Hz, 1H), 7.57 (d, J = 2.3 Hz, 2H), 7.14 (d, J = 8.4 Hz, 1H), 6.97 - 6.87 (m, 2H), 5.14 (s, 2H), 4.20 (t, J = 4.5 Hz, 2H), 3.86 (s, 3H), 3.32 (d, J = 6.3 Hz, 2H), 2.92 (t, J = 6.2 Hz, 2H).

[0235] 7-[(5-methoxypyridin-2-yl)methoxy]-2-(6-methoxypyridine-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline 6-Methoxypyridine-3-carboxylic acid (16 mg, 0.11 mmol) was dissolved in DMF (2 mL), and 7-[(5-methoxypyridin-2-yl)methoxy]-2-(6-methoxypyridine-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline (33 mg, 0.11 mmol), HATU (40.9 mg, 0.11 mmol), and DIPEA (60 μL, 0.32 mmol) were added. The reaction mixture was sonicated for 5 minutes, and the reaction mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (10 mL), and the product was extracted with ethyl acetate (2 × 75 mL). The organic layers were combined and concentrated under reduced pressure. Purification by basic preparative HPLC gave the title compound. 1 H NMR (353K, 250 MHz, DMSO-d6) δ 8.42 - 8.16 (m, 2H), 7.78 (dd, J = 8.5, 2.4 Hz, 1H), 7.50 - 7.24 (m, 2H), 7.18 - 7.01 (m, 1H), 6.94 - Tr (MET-uHPLC-AB-101) = 2.82 min, (ES + ) (M+H) + 406.

[0236] The following was also prepared by this route:

[0237] [Table 4] TIFF0007720847000035.tif220157TIFF0007720847000036.tif224153TIFF00077208470 00037.tif186155TIFF0007720847000038.tif240154TIFF0007720847000039.tif225155

[0238] Method 2 Method 2 scheme

[0239] [ka]

[0240] [Example 2] 7-[(5-methoxypyridin-2-yl)methoxy]-2-[(6-methoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-1-one 7-[(5-methoxypyridin-2-yl)methoxy]-1,2,3,4-tetrahydroisoquinolin-1-one A solution of 7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (150 mg, 0.92 mmol), 2-(bromomethyl)-5-methoxypyridine (204 mg, 1.01 mmol), and potassium carbonate (140 mg, 1.01 mmol) in acetone (15 mL) was heated at 55° C. for 2.5 hours. Additional 2-(bromomethyl)-5-methoxypyridine (102 mg, 0.5 mmol) and potassium carbonate (140 mg, 1.01 mmol) were added, and the reaction was stirred overnight at 55° C. After 20 hours, additional 2-(bromomethyl)-5-methoxypyridine (279 mg, 1.38 mmol) and potassium carbonate (140 mg, 1.01 mmol) were added, and the reaction was stirred overnight at 55° C. The reaction mixture was cooled and diluted with EtOAc (50 mL). The mixture was washed with water (2 x 10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified twice by column chromatography (silica, eluting with 0-20% MeOH in DCM) to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 8.31 - 8.26 (m, 1H), 7.93 (s, 1H), 7.46 - 7.40 (m, 3H), 7.22 (d, J = 8.3 Hz, 1H), 7.12 (dd, J = 8.3, 2.8 Hz, 1H), 5.12 (s, 2H), 3.94 - 3.65 (m, 5H), 2.81 (t, J = 6.6 Hz, 2H). Tr (METCR1410) = 0.89 min, (ES + ) (M+H) + 285, 92%.

[0241] 7-[(5-methoxypyridin-2-yl)methoxy]-2-[(6-methoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-1-one A solution of 7-[(5-methoxypyridin-2-yl)methoxy]-1,2,3,4-tetrahydroisoquinolin-1-one (119 mg, 0.39 mmol) and NaH (60% in oil, 18 mg, 0.46 mmol) in THF (10 mL) was heated to 70° C. for 0.5 h. The reaction mixture was then cooled to room temperature, and 5-(chloromethyl)-2-methoxypyridine (73 mg, 0.46 mmol) in THF and DMF (2:1, 3 mL) was added. The reaction mixture was stirred at room temperature overnight. EtOAc (50 mL) was added, and the mixture was washed with water (2×10 mL). The combined organics were dried (NaSO), filtered, and concentrated in vacuo. The crude residue was purified by preparative HPLC (high pH) to provide the title compound.

[0242] 1 H NMR (500 MHz, chloroform-d) δ 8.31 (d, J = 2.8 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.77 - 7.74 (m, 1H), 7.62 (dd, J = 8.5, 2.5 Hz, 1H), 7.50 - 7.44 (m, 1H), 7.31 - 7.27 (m, 1H), 7.11 - 7.05 (m, 2H), 6.72 (d, J = 8.5 Hz, 1H), 5.22 (s, 2H), 4.70 (s, 2H), 3.93 (s, 3H), 3.88 (s, 3H), 3.46 (t, J = 6.7 Hz, 2H), 2.86 (t, J = 6.7 Hz, 2H). Tr (MET-uHPLC-AB-101) = 2.80 min, (ES + ) (M+H) + 406.

[0243] Method 3 Method 3 scheme

[0244] [ka]

[0245] [Example 3] 7-[(5-methoxypyridin-2-yl)methoxy]-2-(5-methoxypyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinoline To a microwave vial was added 7-[(5-methoxy-2-pyridyl)methoxy]-1,2,3,4-tetrahydroisoquinoline hydrochloride (50 mg, 0.16 mmol, prepared as described in Method 1), DIPEA (80 μL, 0.49 mmol), and 2-chloro-5-methoxy-pyrimidine (28 mg, 0.20 mmol). The vessel was sealed and irradiated at 140 °C for 4 h. The reaction was repeated on a 125 mg scale, and the two portions were combined and concentrated in vacuo. The crude residue was purified by column chromatography (silica, eluting with 20-100% EtOAc in heptane) followed by preparative HPLC (low pH) to give the title compound.

[0246] 1 H NMR (500 MHz, DMSO-d6) δ 8.28 (d, J = 2.4 Hz, 1H), 8.25 - 8.21 (m, 2H), 7.46 (d, J = 8.5 Hz, 1H), 7.41 (dd, J = 8.6, 2.9 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 2.6 Hz, 1H), 6.81 (dd, J = 8.3, 2.7 Hz, 1H), 5.07 (s, 2H), 4.74 (s, 2H), 3.89 (t, J = 5.9 Hz, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 2.76 (t, J = 5.8 Hz, 2H). Tr (MET-uHPLC-AB-101) = 3.37 min, (ES + ) (M+H) + 379.

[0247] Method 4 Method 4 scheme

[0248] [ka]

[0249] [Example 4] 7-[(5-methoxypyridin-2-yl)methoxy]-2-(4-methylpiperazine-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline 7-[(5-Methoxy-2-pyridyl)methoxy]-3,4-dihydro-1H-isoquinoline-2-carbonyl chloride hydrochloride Triphosgene (0.11 g, 0.36 mmol) was dissolved in DCM (5 mL), the reaction was cooled to -78 °C, and pyridine (80 μL, 1.03 mmol) was added, followed by 7-[(5-methoxypyridin-2-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline (278 mg, 1.03 mmol, prepared by Method 1) dissolved in DCM (3 mL). The reaction mixture was warmed to room temperature and stirred for 1.5 h. The reaction mixture was diluted with DCM, 2 M HCl was added, the layers were separated, and the aqueous layer was extracted with DCM (2 × 20 mL). The organic layers were combined and washed with NaHCO3. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (silica, eluting with 0–50% EtOAc in heptane) to give the title compound. 1 H (250 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.27 (d, J = 1.8 Hz, 1H), 7.57 - 7.30 (m, 2H), 7.14 (d, J = 8.4 Hz, 1H), 7.04 - 6.83 (m, 2H), 5.10 (s, 2H), 4.21 (s, 2H), 3.85 (s, 3H), 3.35 (t, J = 6.3 Hz, 2H), 2.95 (t, J =6.4 Hz, 2H). Tr (METCR1410) = 1.12 min, (ES + ) (M+H) + 333, 93%.

[0250] 7-[(5-methoxypyridin-2-yl)methoxy]-2-(4-methylpiperazine-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline 1-Methylpiperazine (15 mg, 0.15 mmol) was dissolved in DCM (2 mL) and NaH (60%, 12 mg, 0.3 mmol) was added. 7-[(5-Methoxy-2-pyridyl)methoxy]-3,4-dihydro-1H-isoquinoline-2-carbonyl chloride hydrochloride (50 mg, 0.15 mmol) was dissolved in DCM (2 mL) and added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (20 mL) and quenched with water. The two layers were separated and the aqueous layer was extracted with DCM (2 x 25 mL). The combined organics were concentrated under reduced pressure. The residue was washed with 2:1 diethyl ether:heptane to give the title compound.

[0251] 1 H NMR (500 MHz, DMSO-d6) δ 8.27 (d, J = 2.2 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.41 (dd, J = 8.6, 2.8 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 6.90 - 6.72 (m, 2H), 5.06 (s, 2H), 4.30 (s, 2H), 3.83 (s, 3H), 3.38 (t, J = 5.9 Hz, 2H), 3.22 - 3.12 (m, 4H), 2.73 (t, J = 5.7 Hz, 2H), 2.33 - 2.27 (m, 4H), 2.18 (s, 3H). Tr (MET-uHPLC-AB-101) = 1.66 min, (ES + ) (M+H) + 397.

[0252] The following was also prepared by this method:

[0253] [Table 5]

[0254] Method 5 Scheme of Method 5

[0255] [ka]

[0256] [Example 5] (6-Methoxypyridin-3-yl)methyl 1,2,3,4-tetrahydroisoquinoline-2-carboxylate 3,4-Dihydro-1H-isoquinoline-2-carbonyl chloride Triphosgene (780 mg, 2.63 mmol) was dissolved in DCM (15 mL) and cooled to -78 °C, and pyridine (0.6 mL, 7.51 mmol) was added, followed by 1,2,3,4-tetrahydroisoquinoline (940 μL, 7.51 mmol). The reaction mixture was warmed to room temperature and stirred for 1.5 h. 2 M HCl (10 mL) was added, and the product was extracted with DCM (3 × 25 mL). The organic layers were combined and washed with saturated NaHCO3. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (silica, eluting with 0-10% EtOAc in heptane) to give the title compound. 1 H NMR (500 MHz, chloroform-d) δ 7.24 - 7.10 (m, 4H), 4.84 (s, 1H), 4.75 (s, 1H), 3.92 (t, J = 6.0 Hz, 1H), 3.85 (t, J = 6.0 Hz, 1H), 3.03 - 2.87 (m, 2H). Tr (METCR1410) = 1.13 min, (ES + ) (M+H) + 196.

[0257] (6-Methoxypyridin-3-yl)methyl 1,2,3,4-tetrahydroisoquinoline-2-carboxylate (6-Methoxy-3-pyridyl)methanol (142 mg, 1.02 mmol) was dissolved in DCM (2 mL) and NaH (60%, 41 mg, 1.02 mmol) was added. 3,4-Dihydro-1H-isoquinoline-2-carbonyl chloride (100 mg, 0.51 mmol) was dissolved in DCM (2 mL) and added to the reaction mixture. The reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with DCM and quenched with water. The two layers were separated and the aqueous layer was extracted with DCM (2 × 25 mL). The combined organics were concentrated under reduced pressure, and the residue was purified by acidic preparative HPLC. Further purification by column chromatography (silica, eluting with 0–50% EtOAc in heptane) gave the title compound.

[0258] 1 H NMR (500 MHz, DMSO-d6) δ 8.21 (d, J = 2.1 Hz, 1H), 7.75 (dd, J = 8.5, 2.4 Hz, 1H), 7.25 - 7.11 (m, 4H), 6.83 (d, J = 8.5 Hz, 1H), 5.06 (s, Tr (MET-uHPLC-AB-101) = 3.45 min, (ES + ) (M+H) + 299.

[0259] The following was also prepared by this method:

[0260] [Table 6]

[0261] Method 6 Scheme of Method 6

[0262] [ka]

[0263] [Example 6] (7-[(5-methoxypyridin-2-yl)methoxy]-2-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline An oven-dried pressure tube fitted with a septum was charged with Pd(dba) (30 mg, 0.03 mmol), RuPhos (30 mg, 0.07 mmol), cesium carbonate (372 mg, 1.14 mmol), 7-[(5-methoxy-2-pyridyl)methoxy]-1,2,3,4-tetrahydroisoquinoline hydrochloride (100 mg, 0.33 mmol, prepared as described in Method 1), and 5-bromo-2-methoxypyridine (67 mg, 0.36 mmol). The vessel was sealed and flushed with nitrogen, and toluene (7.5 mL) was added. The reaction mixture was degassed with nitrogen and then heated at 85 °C overnight. The reaction mixture was cooled, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography (silica, eluting with 0–100% EtOAc in heptane) to give the title compound.

[0264] 1 H NMR (500 MHz, DMSO- d6) δ 8.30 - 8.25 (m, 1H), 7.84 (d, J = 2.9 Hz, 1H), 7.51 (dd, J = 9.0, 3.1 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.42 (dd, J = 8.6, 2.9 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 2.5 Hz, 1H), 6.82 (dd, J = 8.3, 2.7 Hz, 1H), 6.73 (d, J = 9.0 Hz, 1H), 5.07 (s, 2H), 4.25 (s, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.42 (t, J = 5.9 Hz, 2H), 2.80 (t, J = 5.8 Hz, 2H). Tr (MET-uHPLC-AB-101) = 3.15 min, (ES + ) (M+H) + 378.

[0265] The following was also prepared by this method:

[0266] [Table 7]

[0267] Method 7 Scheme of Method 7

[0268] [ka]

[0269] [Example 7] (7-[(5-methoxypyridin-2-yl)methoxy]-2-[(6-methoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydroisoquinoline 7-[(5-Methoxy-2-pyridyl)methoxy]-1,2,3,4-tetrahydroisoquinoline hydrochloride (175 mg, 0.57 mmol, as prepared by Method 450) and cesium carbonate (372 mg, 1.14 mmol) were stirred in DMF (10 mL) until a complete solution was obtained. Potassium iodide (95 mg, 0.57 mmol) and 5-(chloromethyl)-2-methoxy-pyridine (126 mg, 0.8 mmol) were added as a solution in DMF (5 mL), and the reaction mixture was stirred at room temperature for 17 h. The reaction mixture was concentrated in vacuo and then suspended in DCM. Insoluble inorganic material was removed by vacuum filtration, and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography (silica, eluting with 0–100% EtOAc in heptane) to give the title compound.

[0270] 1H NMR (500 MHz, DMSO- d6) δ 8.26 (dd, J = 2.6, 0.9 Hz, 1H), 8.09 (d, J = 2.1 Hz, 1H), 7.67 (dd, J = 8.5, 2.4 Hz, 1H), 7.44 - 7.37 (m, 2H), 6.99 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.76 (dd, J = 8.4, 2.7 Hz, 1H), 6.68 (d, J = 2.6 Hz, 1H), 5.02 (s, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 3.56 (s, 2H), 3.47 (s, 2H), 2.70 (t, J = 5.6 Hz, 2H), 2.63 (t, J = 5.9 Hz, 2H). + ) (M+H) + 392.

[0271] Method 8 Scheme of Method 8

[0272] [ka]

[0273] [Example 8] 2-(5-methoxypyridin-2-yl)-7-[(5-methoxypyridin-2-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline To a microwave vial was added 7-[(5-methoxy-2-pyridyl)methoxy]-1,2,3,4-tetrahydroisoquinoline hydrochloride (100 mg, 0.33 mmol, prepared by Method 1), 2-bromo-5-methoxypyridine (118 mg, 0.63 mmol), potassium t-butoxide (91 mg, 0.81 mmol), CyJohnPhos (7 mg, 0.02 mmol), Pd(OAc) (4 mg, 0.02 mmol), and t-butanol (2 mL). The vial was sealed, degassed with nitrogen, and irradiated at 100 °C for 0.5 h. The reaction was then irradiated at 100 °C for an additional 1 h. The reaction was repeated on a 75 mg scale, and two portions were combined for purification. The reaction mixture was diluted with EtOAc (10 mL) and filtered through Celite. The resulting filtrate was washed with saturated NaCl solution, dried over MgSO4, and concentrated under reduced pressure to give the crude product. The crude residue was purified by column chromatography (silica, eluting with 0-100% EtOAc in heptane) to give the title compound.

[0274] 1 H NMR (500 MHz, DMSO-d6) δ 8.28 (d, J = 2.8 Hz, 1H), 7.89 (d, J = 3.1 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.41 (dd, J = 8.6, 2.9 Hz, 1H), 7.28 (dd, J = 9.1, 3.1 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.91 - 6.83 (m, 2H), 6.80 (dd, J = 8.4, 2.6 Hz, 1H), 5.07 (s, 2H), 4.53 (s, 2H), 3.83 (s, 3H), 3.72 (s, Tr (MET-uHPLC-AB-101) = 2.14 min, (ES + ) (M+H) + 378.

[0275] The following was also prepared by this method:

[0276] [Table 8]

[0277] Method 9 Scheme of Method 9

[0278] [ka]

[0279] [Example 9] 7-[(5-methoxypyridin-2-yl)methoxy]-2-(6-methoxypyridine-3-carbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline 7-(benzyloxy)-2-(6-methoxypyridine-3-carbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline 7-(Benzyloxy)-1-methyl-1,2,3,4-tetrahydroisoquinoline (400 mg, 1.58 mmol), 6-methoxypyridine-3-carboxylic acid (242 mg, 1.58 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (600 mg, 1.58 mmol) were dissolved in DMF (8 mL), and DIPEA (825 μL, 4.74 mmol) was added. The reaction was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction mixture was poured into water, diluted with DCM, and the aqueous layer was extracted into DCM (3 × 20 mL). The combined organic layers were dried and concentrated in vacuo to give the title compound, which was used in the next step without further purification. Tr (METCR1673) = 1.25 minutes, (ES + ) (M+H) + 389, 87%.

[0280] 2-(6-Methoxypyridine-3-carbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-7-ol 7-(Benzyloxy)-2-(6-methoxypyridine-3-carbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline (87%, 870 mg, 1.95 mmol) was dissolved in 1:1 EtOH:THF (20 mL) and placed under a nitrogen atmosphere. Palladium (10% on carbon) (87 mg, 0.82 mmol) was added, and the reaction was placed under a hydrogen atmosphere and stirred at room temperature for 16 hours. The hydrogen was evacuated from the flask, and the reaction mixture was filtered through a pad of Celite and washed with MeOH (30 mL). The filtrate was concentrated and purified by column chromatography (silica, eluting with 0-100% EtOAc in heptane) to give the title compound. Tr (METCR1673) = 0.96 min, (ES + ) (M+H) + 299, 90%.

[0281] 7-[(5-methoxypyridin-2-yl)methoxy]-2-(6-methoxypyridine-3-carbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline 2-(6-Methoxypyridine-3-carbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-7-ol (90%, 229 mg, 0.77 mmol) and (5-methoxypyridin-2-yl)methanol (120 mg, 0.84 mmol) were suspended in toluene (7 mL) and CMBP (0.24 mL, 0.92 mmol) was added. The reaction was heated to 100 °C in a sealed tube for 4 h. The reaction mixture was cooled, diluted with DCM, washed with water, dried (MgSO), and concentrated to dryness. The oily residue was dissolved in EtOAc and heptane was added dropwise to give a precipitate. The mixture was concentrated to dryness, suspended in 1:1 EtOAc:heptane, filtered, and the solid was washed with EtOAc and evaporated to dryness to give the title compound.

[0282] 1H NMR (250 MHz, 353 K, DMSO- d6) δ 8.35 - 8.14 (m, 2H), 7.75 (dd, J = 8.5, 2.4 Hz, 1H), 7.52 - 7.30 (m, 2H), 7.06 (d, J = 8.2 Hz, 1H), 6.93 - 6.79 (m, 3H), 5.31 (s, 1H), 5.08 (s, 2H), 4.00 (s, 1H), 3.93 (s, 3H), 3.85 (s, 3H), 3.50 - 3.29 (m, 1H), 2.95 - 2.80 (m, 1H), 2.76 - 2.64 (m, 1H), 1.49 (d, J = 6.7 Hz, 3H). Tr (MET-uHPLC-AB-101) = 3.15 min, (ES + ) (M+H) + 420.

[0283] Method 10 Scheme of Method 10

[0284] [ka]

[0285] [Example 10] 7-[(5-methoxypyridin-2-yl)methoxy]-2-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydroisoquinolin-3-one 7-[(5-methoxy-2-pyridyl)methoxy]-2,4-dihydro-1H-isoquinolin-3-one 7-Hydroxy-2,4-dihydro-1H-isoquinolin-3-one (250 mg, 1.53 mmol), 2.2 M KI (696 μL), and CsCO (998 mg, 3.06 mmol) were dissolved in DMF (5 mL), and a solution of 2-(chloromethyl)-5-methoxy-pyridine (241 mg, 1.53 mmol) in DMF (5 mL) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue was triturated with water and further purified by column chromatography (silica, eluting with 0-80% EtOAc in heptane) to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 8.28 (d, J = 2.7 Hz, 1H), 7.94 (s, 1H), 7.66 - 7.25 (m, 2H), 7.10 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 2.5 Hz, 1H), 6.89 (dd, J = 8.3, 2.6 Hz, 1H), 5.08 (s, 2H), 4.29 (s, 2H), 3.84 (s, 3H), 3.35 (s, 2H). Tr (METCR1410) = 0.86 min, (ES + ) (M+H) + 285.

[0286] 7-[(5-methoxypyridin-2-yl)methoxy]-2-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydroisoquinolin-3-one A suspension of (1R,2R)-N,N'-dimethylcyclohexane-1,2-diamine (23 mg, 0.16 mmol), copper(I) iodide (10 mg, 0.05 mmol), and potassium phosphate (280 mg, 1.32 mmol) in dioxane (6 mL) was degassed in a pressure tube for 50 minutes. 7-[(5-methoxy-2-pyridyl)methoxy]-2,4-dihydro-1H-isoquinolin-3-one (150 mg, 0.53 mmol) and 5-bromo-2-methoxypyridine (80 μL, 0.63 mmol) were then added, and the reaction vessel was sealed and heated to 110 °C for 21.5 hours. The reaction mixture was cooled, and EtOAc (20 mL) and water (10 mL) were added. The organic phase was extracted, and the aqueous phase was re-extracted with EtOAc (2 × 5 mL). The combined organics were washed with saturated brine solution, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography (silica, eluting with 0-100% EtOAc in heptane) to give the title compound.

[0287] 1H NMR (500 MHz, DMSO-d6) 8.27 (d, J = 2.8 Hz, 1H), 8.14 (d, J = 2.7 Hz, 1H), 7.69 (dd, J = 8.8, 2.7 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.41 (dd, J = 8.6, 2.9 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.95 (dd, J = 8.3, 2.6 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 5.09 (s, 2H), 4.82 (s, 2H), 3.90 - 3.79 (m, 6H), 3.64 (s, 2H). Tr (MET-uHPLC-AB-101) = 2.5 min, (ES + ) (M+H) + 392.

[0288] Method 11 Scheme of Method 11

[0289] [ka]

[0290] [Example 11] 5-Methoxy-N-[2-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridine-2-carboxamide 2-(6-Methoxy-3-pyridyl)-7-nitro-3,4-dihydro-1H-isoquinoline 7-Nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (500 mg, 2.33 mmol), RuPhos Pd G3 (195 mg, 0.23 mmol), RuPhos (109 mg, 0.23 mmol), sodium 2-methylpropan-2-olate (784 mg, 8.15 mmol), and 5-bromo-2-methoxy-pyridine (657 mg, 3.49 mmol) were suspended in degassed THF (20 mL). The vial was sealed, and the resulting mixture was heated at 85 °C for 17 h. The reaction was cooled and diluted with EtOAc. The resulting solution was filtered through a pad of Celite and concentrated. Further purification by column chromatography (silica, 0–100% EtOAc in heptane) afforded the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 8.15 (d, J = 2.3 Hz, 1H), 8.04 (dd, J = 8.4, 2.4 Hz, 1H), 7.90 (d, J = 3.0 Hz, 1H), 7.56 (dd, J = 9.0, 3.1 Hz, 1H), 7.46 (d. (METCR1410) = 1.16 minutes, (ES + ) (M+H) + 286.

[0291] 2-(6-Methoxy-3-pyridyl)-3,4-dihydro-1H-isoquinolin-7-amine A solution of 2-(6-methoxy-3-pyridyl)-7-nitro-3,4-dihydro-1H-isoquinoline (100 mg, 0.35 mmol) in EtOH (5 mL). The mixture was degassed and purged with nitrogen three times. Pd / C (10%, 19 mg, 0.02 mmol) was added, and the reaction mixture was degassed and purged with nitrogen three more times, then filled with hydrogen three times. The reaction was stirred for 16 hours overnight. The mixture was then filtered through Celite, washed with MeOH, and then concentrated in vacuo to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ 7.84 (d, J = 3.0 Hz, 1H), 7.50 (dd, J = 9.0, 3.1 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 9.0 Hz, 1H), 6.52 - 6.31 (m, 2H), 4.85 (s, 2H), 4.14 (s, 2H), 3.78 (s, 3H), 3.38 (t, J = 5.9 Hz, 2H), 2.71 (t, J = 5.7 Hz, 2H). Tr (METCR1410) = 0.79 min, (ES + ) (M+H) + 256, 84%.

[0292] 5-Methoxy-N-[2-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridine-2-carboxamide 5-Methoxypyridine-2-carboxylic acid (30 mg, 0.2 mmol) was dissolved in DMF (1 mL), and HATU (74 mg, 0.2 mmol) and DIPEA (0.7 mL, 4.03 mmol) were added. A solution of 2-(6-methoxy-3-pyridyl)-3,4-dihydro-1H-isoquinolin-7-amine (50 mg, 0.2 mmol) in DMF (1 mL) was added to the reaction mixture and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was triturated with water (2 mL). Purification by basic preparative HPLC gave the title compound.

[0293] 1H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.38 (d, J = 2.7 Hz, 1H), 8.12 (d, J = 8.7 Hz, 1H), 7.88 (d, J = 3.0 Hz, 1H), 7.78 (m, 1H), 7.69 - 7.58 (m, 2H), 7.55 (dd, J = 9.0, 3.1 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 6.74 (d, J = 8.9 Hz, 1H), 4.29 (s, 2H), 3.94 (s, 3H), 3.78 (s, 3H), 3.45 (t, J = 5.9 Hz, 2H), 2.87 (t, J = 5.7 Hz, 2H). Tr (METCR1603) = 4.71 min, (ES + ) (M+H) + 391.

[0294] Method 12 Scheme of Method 12

[0295] [ka]

[0296] [Example 12] (5-Methoxy-N-[2-(6-methoxypyridine-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridine-2-carboxamide tert-Butyl-7-[(5-methoxypyridine-2-carbonyl)amino]-3,4-dihydro-1H-isoquinoline-2-carboxylate 5-Methoxypyridine-2-carboxylic acid (308 mg, 2.01 mmol) was dissolved in DMF (5 mL), and HATU (766 mg, 2.01 mmol) and DIPEA (0.7 mL, 4.03 mmol) were added. A solution of tert-butyl-7-amino-3,4-dihydro-1H-isoquinoline-2-carboxylate (500 mg, 2.01 mmol) in DMF (5 mL) was added to the reaction mixture and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was diluted with water (10 mL), which was extracted with EtOAc (2 × 20 mL). The organic layers were combined and concentrated in vacuo. Purification by column chromatography (silica, 0-80% EtOAc in heptane) gave the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.38 (d, J = 2.9 Hz, 1H), 8.12 (d, J = 8.7 Hz, 1H), 7.87 - 7.48 (m, 3H), 7.13 (d, J = 8.3 Hz, 1H), 4.48 (s, 2H), 3.93 (s, 3H), 3.55 (t, J = 5.8 Hz, 2H), 2.74 (t, J = 5.8 Hz, 2H), 1.43 (s, 9H); + ) (M+H-tBu) + 328.

[0297] 5-Methoxy-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyridine-2-carboxamide hydrochloride tert-Butyl-7-[(5-methoxypyridine-2-carbonyl)amino]-3,4-dihydro-1H-isoquinoline-2-carboxylate (500 mg, 1.3 mmol) was suspended in 4 M HCl in dioxane (9.8 mL) and sonicated. The suspension was stirred at room temperature overnight. The resulting material was filtered to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ 10.46 (s, 1H), 9.29 (s, 2H), 8.38 (d, J = 2.8 Hz, 1H), 8.12 (d, J = 8.7 Hz, 1H), 7.80 (d, J = 1.8 Hz, 1H), 7.70 (dd, J = 8.4, 2.1 Hz, 1H), 7.62 (dd, J = 8.8, 2.9 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 4.26 (t, J = 4.5 Hz, 2H), 3.93 (s, 3H), 3.40 - 3.28 (m, 2H), 2.97 (t, J = 6.2 Hz, 2H). Tr (METCR1410) = 0.81 min, (ES + ) (M+H) + 284.

[0298] (5-Methoxy-N-[2-(6-methoxypyridine-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridine-2-carboxamide 6-Methoxypyridine-3-carboxylic acid (48 mg, 0.31 mmol) was dissolved in DMF (2 mL), and HATU (119 mg, 0.31 mmol) and DIPEA (0.11 mL, 0.63 mmol) were added. In a 12 mL vial, 5-methoxy-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyridine-2-carboxamide hydrochloride (100 mg, 0.31 mmol) was suspended in DMF (2 mL), and DIPEA (50 μL, 0.31 mmol) was added. The solution was added to the reaction mixture and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was treated with water (5 mL), then acetonitrile (2 mL), and finally MeOH (2 mL) to give the title compound.

[0299] 1H NMR (250 MHz, 353 K, DMSO-d6) δ 10.12 (s, 1H), 8.37 (d, J = 2.5 Hz, 1H), 8.31 (d, J = 1.8 Hz, 1H), 8.11 (d, J = 8.7 Hz, 1H), 7.80 (dd, J = 8.5, 2.4 Hz, 1H), 7.71 - 7.39 (m, 3H), 7.17 (d, J = 8.9 Hz, 1H), 6.88 (dd, J = 8.5, 0.6 Hz, 1H), 4.70 (s, 2H), 3.95 (m, 6H), 3.74 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 5.9 Hz, 2H). Tr (MET-uHPLC-AB-101) = 3.17 min, (ES + ) (M+H) + 419.

[0300] Method 13 Method 13 scheme

[0301] [ka]

[0302] [Example 13] (5-Methoxy-N-[2-(6-methoxypyridine-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-N-methylpyridine-2-carboxamide To a stirred solution of 5-methoxy-N-[2-(6-methoxypyridine-3-carbonyl)-3,4-dihydro-1H-isoquinolin-7-yl]pyridine-2-carboxamide (90%, 50 mg, 0.11 mmol, prepared as described in Method 12) in DMF (5 mL) at 0° C. was added NaH (60% in oil) (60%, 5 mg, 0.13 mmol). The reaction was stirred at room temperature for 10 minutes and iodomethane (10 μL, 0.1 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. Water (5 mL) was added and the reaction mixture was concentrated in vacuo. Purification by acidic preparative HPLC gave the title compound.

[0303] 1 H NMR (250 MHz, 353 K, DMSO-d6) δ 8.40 - 8.21 (m, 1H), 8.05 (d, J = 2.5 Hz, 1H), 7.76 (dd, J = 8.5, 2.4 Hz, 1H), 7.60 - 7.43 (m, 1H), 7.33 (dd, J = 8.7, 2.9 Hz, 1H), 7.21 - 6.56 (m, 4H), 4.60 (s, 2H), 3.94 (s, 3H), 3.82 (s, 3H), 3.68 (t, J = 6.0 Hz, 2H), 3.35 (s, 3H), 2.82 (t, J = 6.0 Hz, 2H). (METCR1603) = 3.68 minutes, (ES + ) (M+H) + 433.

[0304] Method 15 Scheme of Method 15

[0305] [ka]

[0306] [Example 15] 5-{7-[(5-methoxypyridin-2-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-2-carbonyl}-1-methyl-1,2-dihydropyrazin-2-one 4-Methyl-5-oxo-4,5-dihydropyrazine-2-carboxylic acid To a solution of methyl 4-methyl-5-oxo-4,5-dihydropyrazine-2-carboxylate (2.0 g, 10.3 mmol) in THF (30 mL) and MeOH (30 mL) was added 1 M NaOH (22.6 mL, 22.6 mmol) at room temperature, and the reaction was stirred for 96 hours. The solvent was removed in vacuo. 1 M HCl (23 mL) was added at 0° C. The suspension was stirred at 0° C. for 30 minutes. The material was filtered and dried under high vacuum at 40° C. for 4 hours to give the title compound. The crude product was used without further purification. 1H NMR (250 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.97 (d, J = 0.9 Hz, 1H), 3.49 (s, 3H). Tr (METCR1410) = solvent front, (ES + ) (M+H) + = 155.

[0307] 5-{7-[(5-methoxypyridin-2-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-2-carbonyl}-1-methyl-1,2-dihydropyrazin-2-one To a mixture of HATU (185 mg, 0.49 mmol), 4-methyl-5-oxo-4,5-dihydropyrazine-2-carboxylic acid (50 mg, 0.32 mmol) in DMF (4 mL) was added DIPEA (0.11 mL, 0.65 mmol) at 0° C. The reaction was stirred at room temperature for 30 minutes. 7-[(5-methoxypyridin-2-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline hydrochloride (110 mg, 0.36 mmol) was added. The reaction was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was suspended in water (20 mL). The suspension was stirred at room temperature for 30 minutes. The material was filtered, washed with water, and purified by low pH preparative HPLC. Pure fractions were combined, and the solvent was removed by lyophilization to give the title compound.

[0308] 1 H NMR (500 MHz, DMSO-d6) δ 8.31 - 8.25 (m, 1H), 8.19 (s, 1H), 7.96 (s, 1H), 7.43 (m, 2H), 7.08 (d, J = 8.5 Hz, 1H), 6.83 (m, 2H), 5.06 (m, 2H), 4.71 (s, 2H), 3.83 (s, 3H), 3.79 (s, 2H), 3.48 (s, 3H), 2.80 (s, 2H). Tr (METCR1603) = 3.48 min, (ES + ) (M+H) + = 407.

[0309] Method 16 Scheme of Method 16

[0310] [ka]

[0311] [Example 16] 7-[(5-methoxypyridin-2-yl)methoxy]-2-(6-methoxypyridine-3-carbonyl)-1,2,3,4-tetrahydro-2,6-naphthyridine 7-chloro-2-(6-methoxypyridine-3-carbonyl)-1,2,3,4-tetrahydro-2,6-naphthyridine To a mixture of HATU (558 mg, 1.47 mmol) and 6-methoxypyridine-3-carboxylic acid (150 mg, 0.98 mmol) in DMF (8 mL) was added DIPEA (340 μL, 1.96 mmol) at 0° C. The reaction was stirred at room temperature for 30 minutes. 7-Chloro-1,2,3,4-tetrahydro-2,6-naphthyridine hydrochloride (221 mg, 1.08 mmol) was added. The reaction was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was partitioned between EtOAc (20 mL) and water (30 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, evaporated under reduced pressure, and the residue was washed with MeCN. The residue was purified by low pH preparative HPLC. The pure fractions were combined, and the solvent was removed in vacuo to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 8.32 (d, J = 2.1 Hz, 1H), 8.25 (s, 1H), 7.82 (dd, J = 8.5, 2.0 Hz, 1H), 7.47 (s, 1H), 6.90 (d, J = 8.5 Hz, 1H), 4.75 (s, 2H), 3.91 (s, 3H), 3.66 (s, 2H), 2.88 (t, J = 5.7 Hz, 2H). Tr (METCR1410) = 0.97 min, (ES + ) (M+H) + = 304.

[0312] 7-[(5-methoxypyridin-2-yl)methoxy]-2-(6-methoxypyridine-3-carbonyl)-1,2,3,4-tetrahydro-2,6-naphthyridine A sealed tube was charged with cesium carbonate (322 mg, 1.00 mmol) and heated to dryness under vacuum. The tube was cooled under nitrogen, and 7-chloro-2-(6-methoxypyridine-3-carbonyl)-1,2,3,4-tetrahydro-2,6-naphthyridine (100 mg, 0.33 mmol), Pd2(dba)3 (15 mg, 0.02 mmol), and BrettPhos (22 mg, 0.04 mmol) were added. Toluene (4 mL) was added via syringe. The reaction mixture was degassed with nitrogen for 5 minutes. (5-Methoxypyridin-2-yl)methanol (928 mg, 0.66 mmol) was added, and the reaction mixture was stirred at 100 °C for 20 hours. The reaction was cooled to room temperature and quenched with water (15 mL). The aqueous phase was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered, evaporated under reduced pressure, and the residue was purified by low pH preparative HPLC to give the title compound.

[0313] 1 H NMR (500 MHz, DMSO-d6) δ 8.31 (d, J = 2.2 Hz, 1H), 8.25 (s, 1H), 7.99 (s, 1H), 7.81 (dd, J = 8.5, 1.9 Hz, 1H), 7.37 (s, 2H), 6.90 (d, J = 8.5 Hz, 1H), 6.83 (s, 1H), 5.31 (s, 2H), 4.72 (s, 2H), 3.90 (s, 3H), 3.81 (s, 3H), 3.65 (d, J = 20.2 Hz, 2H), 2.81 (t, J = 5.8 Hz, 2H). Tr (METCR1603) = 3.73 minutes, (ES + ) (M+H) + = 407.

[0314] Method 17 Scheme of Method 17

[0315] [ka]

[0316] [Example 17] 5-Methoxy-N-[2-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-N-methylpyridine-2-carboxamide To a stirred solution of 5-methoxy-N-[2-(6-methoxy-3-pyridyl)-3,4-dihydro-1H-isoquinolin-7-yl]pyridine-2-carboxamide (95%, 30 mg, 0.07 mmol) in DMF (2 mL) was added NaH (60% in oil) (60%, 3.5 mg, 0.09 mmol) at 0° C. The reaction was stirred at room temperature for 10 minutes, and iodomethane (2 μL, 0.04 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. Water (5 mL) was added to the reaction mixture, and the mixture was concentrated in vacuo. The crude residue was washed with water (2 mL) and purified by acidic preparative HPLC to provide the title compound.

[0317] 1 H NMR (250 MHz, 353 K, DMSO-d6) δ 8.05 (d, J = 2.8 Hz, 1H), 7.82 (d, J = 3.0 Hz, 1H), 7.60 - 7.37 (m, 2H), 7.32 (dd, J = 8.7, 2.9 Hz, 1H), 7.17 - 6.96 (m, 2H), 6.91 (dd, J = 8.0, 2.3 Hz, 1H), 6.70 (d, J = 8.9 Hz, 1H), 4.19 (s, 2H), 3.93 - 3.73 (m, 6H), 3.58 - 3.31 (m, 5H), 2.83 (t, J = 5.9 Hz, 2H). Tr (MET-uHPLC-AB-101) = 2.67 min, (ES + ) (M+H) + 405.

[0318] Method 18 Scheme of Method 18

[0319] [ka]

[0320] [Example 18] 7-[(5-methoxypyridin-2-yl)methoxy]-2-[(6-methoxypyridin-3-yl)sulfonyl]-1,2,3,4-tetrahydroisoquinoline To a vial was added 7-[(5-methoxy-2-pyridyl)methoxy]-1,2,3,4-tetrahydroisoquinoline hydrochloride (prepared by Method 1) (50 mg, 0.16 mmol), DIPEA (90 μL, 0.57 mmol), and DCM (2 mL) at room temperature, and the mixture was stirred. 4-tert-Butylbenzenesulfonyl chloride (41 mg, 0.20 mmol) was added, the vial was purged with nitrogen, sealed, and the reaction was stirred for 45 minutes. Water (2 mL) was added, and the organic layer was separated. The aqueous layer was extracted with DCM (3 × 2 mL), and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the crude product. The product was purified by column chromatography (silica, eluting with 0–50% EtOAc in heptane) to give the title compound.

[0321] 1 H NMR (500 MHz, chloroform-d) δ 8.64 (d, J = 2.5 Hz, 1H), 8.29 (d, J = 2.8 Hz, 1H), 7.92 (dd, J = 8.8, 2.5 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 7.21 (dd, J = 8.6, 2.9 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.84 - 6.77 (m, 2H), 6.64 (d, J = 2.5 Hz, 1H), 5.09 (s, 2H), 4.24 (s, 2H), 4.00 (s, 3H), 3.87 (s, 3H), 3.37 (t, J = 5.9 Hz, 2H), 2.85 (t, J = 5.9 Hz, 2H). Tr (MET-uHPLC-AB-101) = 3.37 min, (ES +) (M+H) + 442.

[0322] Method 19 Scheme of Method 19

[0323] [ka]

[0324] [Example 19] 7-{2-[(5-methoxypyridin-2-yl)oxy]ethoxy}-2-(6-methoxypyridine-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline tert-Butyl 7-[2-[(5-methoxy-2-pyridyl)oxy]ethoxy]-3,4-dihydro-1H-isoquinoline-2-carboxylate tert-Butyl 7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (54 mg, 0.22 mmol), KI (36 mg, 0.22 mmol), and CsCO (140 mg, 0.43 mmol) were dissolved in DMF (3 mL), and a solution of 6-methoxy-2,3-dihydrooxazolo[3,2-a]pyridin-4-ium bromide (50 mg, 0.22 mmol) in DMF (2 mL) was added. The reaction mixture was stirred at room temperature overnight. 6-Methoxy-2,3-dihydrooxazolo[3,2-a]pyridin-4-ium bromide (110 mg, 0.46 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was washed with water and further purified by basic preparative HPLC to give the title compound. Tr (METCR1410) = 1.12 min, (ES + ) (M+H) + 401, 87%.

[0325] 7-[2-[(5-methoxy-2-pyridyl)oxy]ethoxy]-1,2,3,4-tetrahydroisoquinoline hydrochloride tert-Butyl 7-[2-[(5-methoxy-2-pyridyl)oxy]ethoxy]-3,4-dihydro-1H-isoquinoline-2-carboxylate (40 mg, 0.10 mmol) was suspended in 4 M HCl in dioxane (2.2 mL), sonicated, and stirred at room temperature for 15 minutes. The precipitate was collected and evaporated to dryness to give the title compound. Tr (METCR1410) = 0.74 min, (ES + ) (M+H) + 301.

[0326] 7-{2-[(5-methoxypyridin-2-yl)oxy]ethoxy}-2-(6-methoxypyridine-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline 6-Methoxypyridine-3-carboxylic acid (14 mg, 0.090 mmol) was dissolved in DMF (1 mL), and HATU (34 mg, 0.090 mmol) and DIPEA (3 μL, 0.18 mmol) were added. 7-[2-[(5-methoxy-2-pyridyl)oxy]ethoxy]-1,2,3,4-tetrahydroisoquinoline hydrochloride (30 mg, 0.090 mmol) was suspended in DMF (2 mL) in a 12 mL vial, and DIPEA (20 μL, 0.09 mmol) was added. The solution was added to the reaction mixture, which was stirred at room temperature under a nitrogen atmosphere for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (5 mL) and extracted into ethyl acetate (2 × 5 mL). The organic layers were combined and concentrated under reduced pressure. Purification by basic preparative HPLC afforded the title compound.

[0327] 1H NMR (250 MHz, 353 K, DMSO-d6) δ 8.29 (d, J = 1.9 Hz, 1H), 7.78 (dd, J = 8.5, 2.4 Hz, 1H), 7.31 - 7.23 (m, 2H), 7.11 - 7.04 (m, 1H), 6.90 - 6.84 (m, 1H), 6.81 - 6.75 (m, 2H), 6.38 - 6.31 (m, 1H), 4.65 (s, 2H), 4.27 - 4.16 (m, 4H), 3.94 (s, 3H), 3.69 (t, J = 6.0 Hz, 2H), 3.65 (s, 3H), 2.84 - 2.77 (m, 2H). Tr (MET-uHPLC-AB-101) = 2.51 min, (ES + ) (M+H) + 436.

[0328] method 20 Method 20 scheme

[0329] [ka]

[0330] [Example 20] 5-Methoxy-2-{[7-(6-methoxypyridine-3-carbonyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-2-yl]methoxy}pyridine 7-tert-Butyl 2-ethyl 5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2,7-dicarboxylate To a solution of ethyl imidazo[1,2-a]pyrazine-2-carboxylate (500 mg, 2.62 mmol) in 15 mL of ethanol was added BocO (1500 mg, 6.8 mmol) and Pd / C (10%, 100 mg, 0.09 mmol) under a hydrogen atmosphere. The mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, eluting with 0-100% methanol in DCM) to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ 7.84 (s, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.13 - 3.89 (m, 2H), 3.77 (t, J = 5.4 Hz, 2H), 3.18 (d, J = 5.2 Hz, 2H), 1.44 (s, 9H), 1.26 (t, J = 7.1 Hz, 3H). Tr (METCR1410) = 0.96 min m / z (ES + ) (M+H) + 296, 78%.

[0331] tert-Butyl 2-(hydroxymethyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-7-carboxylate To a stirred solution of 7-tert-butyl 2-ethyl 5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2,7-dicarboxylate (78%, 600 mg, 2.03 mmol) in anhydrous THF (20 mL) was added lithium aluminum hydride (2.4 M in THF, 850 μL) at 0 °C. The mixture was stirred at the same temperature for 30 min. The reaction mixture was quenched with saturated sodium sulfate solution. The mixture was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica, eluted with 0-100% MeOH in DCM) to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 6.92 (s, 1H), 4.48 (s, 2H), 4.29 (d, J = 5.3 Hz, 2H), 4.09 (q, J = 5.2 Hz, 1H), 3.93 (t, J = 5.5 Hz, 2H), 3.73 (t, J = 5.4 Hz, 2H), 1.44 (s, 9H). Tr (METCR1410) = 0.68 min m / z (ES + ) (M+H) + 254, 89%.

[0332] tert-Butyl 2-{[(5-methoxypyridin-2-yl)oxy]methyl}-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-7-carboxylate tert-Butyl 2-(hydroxymethyl)-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carboxylate (200 mg, 0.79 mmol), 5-methoxypyridin-2-ol (109 mg, 0.87 mmol), and CMBP (0.31 mL, 1.18 mmol) were suspended in anhydrous toluene (6 mL), and the reaction was heated to 100° C. under a nitrogen atmosphere for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo, and the residue was purified by column chromatography (silica, eluting with 0-100% EtOAc in heptane) to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 7.86 (d, J = 3.1 Hz, 1H), 7.38 (dd, J = 8.9, 3.1 Hz, 1H), 7.14 (s, 1H), 6.74 (d, J = 8.9 Hz, 1H), 5.07 (s, 2H), 4.52 (s, 2H), 4.10 - 3.92 (m, 2H), 3.76 (m, 5H), 1.44 (s, 9H). Tr (METCR1410) = 0.95 min m / z (ES + ) (M+H) + 361, 88%.

[0333] 2-({5H,6H,7H,8H-imidazo[1,2-a]pyrazin-2-yl}methoxy)-5-methoxypyridine tert-Butyl 2-[(5-methoxy-2-pyridyl)oxymethyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carboxylate (100 mg, 0.28 mmol) was stirred in a solution of 4 M HCl in dioxane (6 mL) for 1 h. The reaction mixture was concentrated to dryness and dissolved in water (1 mL). The solution was neutralized with saturated aqueous KCO and extracted into DCM (3 x 5 mL). The combined organics were dried over MgSO and concentrated to give the title compound. Tr (METCR1600) = 1.30 min m / z (ES + ) (M+H) + 261.

[0334] 5-Methoxy-2-{[7-(6-methoxypyridine-3-carbonyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazin-2-yl]methoxy}pyridine 6-Methoxypyridine-3-carboxylic acid (35 mg, 0.23 mmol) was dissolved in DMF (1 mL) and HATU (88 mg, 0.23 mmol) and DIPEA (80 μL, 0.46 mmol) were added. A solution of 2-[(5-methoxy-2-pyridyl)oxymethyl]-5H,6H,7H,8H-tetrahydroimidazo[1,2-a]pyrazine (60 mg, 0.23 mmol) in DMF (1 mL) was added and the reaction was stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo and the residue was diluted with water (5 mL). The mixture was extracted with ethyl acetate (2 × 5 mL). The organic layers were combined and concentrated in vacuo. Purification by basic preparative HPLC gave the title compound.

[0335] 1 H NMR (250 MHz, 353 K DMSO-d6) δ 8.34 (d, J = 1.8 Hz, 1H), 8.01 - 7.69 (m, 2H), 7.35 (dd, J = 8.9, 3.1 Hz, 1H), 7.10 (s, 1H), 6.89 (d, J = Tr (METCR1603) = 3.35 minutes, (ES + ) (M+H) + 396.

[0336] Method 21 Method 21 scheme

[0337] [ka]

[0338] Methyl 6-(2-methoxyethoxy)pyridine-3-carboxylate Methyl 6-hydroxypyridine-3-carboxylate (0.10 g, 0.65 mmol) was dissolved in toluene (3 mL) and stirred. 2-Methoxyethanol (70 μL, 0.85 mmol) was added, followed by CMBP (0.22 mL, 0.85 mmol). The mixture was sealed and stirred at 70 °C under a nitrogen atmosphere for 2.5 h. The solvent was removed under reduced pressure, and water (10 mL) was added to the reaction mixture, which was extracted with DCM (3 × 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to give the crude product. The product was purified by column chromatography (silica, eluting with 0–50% EtOAc in heptane) to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 8.73 (d, J = 2.4 Hz, 1H), 8.17 (dd, J = 8.7, 2.4 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 4.48 - 4.43 (m, 2H), 3.84 (s, 3H), 3.69 - 3.65 (m, 2H), 3.29 (s, 3H).

[0339] Methyl 1-(2-methoxyethyl)-6-oxo-pyridine-3-carboxylate Methyl 1-(2-methoxyethyl)-6-oxo-pyridine-3-carboxylate was obtained as a by-product from the previous step. 1 H NMR (500 MHz, DMSO-d6) δ 8.39 (d, J = 2.5 Hz, 1H), 7.80 (dd, J = 9.5, 2.6 Hz, 1H), 6.44 (d, J = 9.5 Hz, 1H), 4.16 (t, J = 5.2 Hz, 2H), 3.79 (s, 3H), 3.57 (t, J = 5.2 Hz, 2H), 3.23 (s, 3H).

[0340] 6-(2-Methoxyethoxy)pyridine-3-carboxylic acid Methyl 6-(2-methoxyethoxy)pyridine-3-carboxylate (25 mg, 0.12 mmol) was dissolved in 1,4-dioxane (1 mL) and treated with 2 M NaOH (0.30 mL, 0.59 mmol). The reaction mixture was stirred for 4 hours. The reaction mixture was concentrated under reduced pressure, and water (5 mL) was added. It was then extracted with IPA:CHCl (3:1, 3 × 10 mL), and the combined organic layers were dried over MgSO, filtered, and concentrated to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 8.69 (d, J = 2.1 Hz, 1H), 8.13 (dd, J = 8.7, 2.3 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 4.47 - 4.42 (m, 2H), 3.70 - 3.65 (m, 2H), 3.29 (s, 3H).

[0341] 1-(2-Methoxyethyl)-6-oxo-pyridine-3-carboxylic acid 1-(2-Methoxyethyl)-6-oxo-pyridine-3-carboxylic acid was also prepared by the previous step. 1 H NMR (500 MHz, DMSO-d6) δ 12.81 (s, 1H), 8.32 (d, J = 2.4 Hz, 1H), 7.78 (dd, J = 9.5, 2.5 Hz, 1H), 6.41 (d, J = 9.5 Hz, 1H), 4.14 (t, J = 5.2 Hz, 2H), 3.57 (t, J = 5.2 Hz, 2H), 3.24 (s, 3H).

[0342] Method 22 Method 22 scheme

[0343] [ka]

[0344] Methyl 6-allyloxypyridine-3-carboxylate To a solution of prop-2-en-1-ol (37 mg, 0.64 mmol) and DMF (2 mL) was added NaH (23 mg, 0.58 mmol) under a nitrogen atmosphere at 0 °C and stirred for 10 minutes. Methyl 6-chloropyridine-3-carboxylate (100 mg, 0.58 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture, which was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give the crude product. The product was purified by high-pH preparative HPLC to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 8.74 (d, J = 2.0 Hz, 1H), 8.22 - 8.15 (m, 1H), 6.96 (d, J = 8.6 Hz, 1H), 6.13 - 6.01 (m, 1H), 5.42 - 5.35 (m, 1H), 5.29 - 5.22 (m, 1H), 4.90 (dt, J = 5.4, 1.4 Hz, 2H), 3.84 (s, 3H).

[0345] 6-Allyloxypyridine-3-carboxylic acid Methyl 6-allyloxypyridine-3-carboxylate (26 mg, 0.14 mmol) and allyl 6-allyloxypyridine-3-carboxylate (18 mg, 0.08 mmol) were dissolved in 1,4-dioxane (2 mL) and treated with 2 M NaOH (27 mg, 0.67 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and water was added. The product was acidified with 1 M HCl (pH = 3), which produced a precipitate. The mixture was concentrated under reduced pressure to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ 8.71 (d, J = 2.3 Hz, 1H), 8.15 (dd, J = 8.7, 2.4 Hz, 1H), 6.93 (d, J = 8.7 Hz, 1H), 6.13 - 6.01 (m, 1H), 5.38 (dd, J = 17.3, 1.7 Hz, 1H), 5.25 (dd, J = 10.5, 1.5 Hz, 1H), 4.89 (dt, J = 5.4, 1.4 Hz, 2H).

[0346] Method 23 Method 23 scheme

[0347] [ka]

[0348] Methyl 6-(2-fluoroethoxy)pyridine-3-carboxylate Methyl 6-hydroxypyridine-3-carboxylate (100 mg, 0.65 mmol) was dissolved in toluene (3 mL) and stirred. 2-Fluoroethanol (50 μL, 0.85 mmol) was added, followed by CMBP (220 μL, 0.85 mmol). The mixture was sealed and stirred at 70° C. under a nitrogen atmosphere for 2.5 hours. The solvent was removed under reduced pressure to give a yellow / brown oil. Water was added to the reaction mixture, which was extracted with DCM (3×10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (silica, eluting with 0–70% EtOAc in heptane) to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 8.74 (d, J = 2.4 Hz, 1H), 8.19 (dd, J = 8.7, 2.4 Hz, 1H), 6.99 (d, J = 8.7 Hz, 1H), 4.84 - 4.78 (m, 1H), 4.74 - 4.69 (m, 1H), 4.65 - 4.60 (m, 1H), 4.59 - 4.53 (m, 1H), 3.85 (s, 3H).

[0349] 6-(2-fluoroethoxy)pyridine-3-carboxylic acid Methyl 6-(2-fluoroethoxy)pyridine-3-carboxylate (50 mg, 0.25 mmol) was dissolved in 1,4-dioxane (2 mL) and treated with 2 M NaOH (0.63 mL, 1.26 mmol). The reaction mixture was stirred for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and water (5 mL) was added. The product was acidified with 1 M HCl (pH = 3). The mixture was concentrated under reduced pressure to give the title compound. 1 H NMR (250 MHz, DMSO-d6) δ 8.71 (d, J = 1.7 Hz, 1H), 8.16 (dd, J = 8.7, 2.4 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 4.92 - 4.78 (m, 1H), 4.72 - 4.61 (m, 2H), 4.54 - 4.47 (m, 1H).

[0350] Method 24 Method 24 scheme

[0351] [ka]

[0352] [Example 24] 6-[6-(1H-imidazol-1-yl)pyridine-3-carbonyl]-3-[(5-methoxypyridin-2-yl)methoxy]-5,6,7,8-tetrahydro-1,6-naphthyridine 6-Imidazol-1-ylpyridine-3-carboxylic acid (33 mg, 0.17 mmol) was dissolved in DMF (2 mL), and HATU (65 mg, 0.17 mmol) and DIPEA (40 μL, 0.23 mmol) were added at room temperature under a nitrogen atmosphere. 3-[(5-Methoxy-2-pyridyl)methoxy]-5H,6H,7H,8H-tetrahydro-1,6-naphthyridine hydrochloride (prepared as described in Method 1) (50 mg, 0.16 mmol) was suspended in DMF (2 mL), and DIPEA (40 μL, 0.23 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was triturated with water (5 mL) and ethanol (2 mL) to give the title compound.

[0353] 1 H NMR (250 MHz, 353 K, DMSO-d6) δ 8.60 (dd, J = 1.6 Hz, 1H), 8.53 (s, 1H), 8.28 (d, J = 2.2 Hz, 1H), 8.19 (d, J = 2.8 Hz, 1H), 8.09 (dd, J = 8.4, 2.3 Hz, 1H), 7.98 - 7.93 (m, 1H), 7.86 (dd, J = 8.4, 0.7 Hz, 1H), 7.50 - 7.37 (m, 2H), 7.34 (d, 1H), 7.17 - 7.12 (m, 1H), 5.15 (s, 2H), 4.75 (s, 2H), 3.88 - 3.77 (m, 5H), 2.92 (t, J = 6.1 Hz, 2H). Tr (MET-uHPLC-AB-105) = 2.22 min, (ES + ) (M+H) + 443.

[0354] The following compounds were prepared similarly:

[0355] [Table 9]

[0356] Method 25 Method 25 scheme

[0357] [ka]

[0358] [Example 25] 7-[(5-methoxypyridin-2-yl)methoxy]-4-(6-methoxypyridine-3-carbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (7-benzyloxy-3,5-dihydro-2H-1,4-benzoxazepin-4-yl)-(6-methoxy-3-pyridyl)methanone 7-Benzyloxy-2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride (200 mg, 0.69 mmol) was added to a stirred solution of 6-methoxypyridine-3-carboxylic acid (110 mg, 0.72 mmol), DIPEA (0.35 mL, 2.06 mmol), and HATU (313 mg, 0.82 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, and the residue was dissolved in water (2 mL) and extracted into DCM (3 × 5 mL). The combined organics were dried (phase separation cartridge) and concentrated in vacuo. The crude residue was purified by column chromatography (silica, eluting with 20–100% EtOAc in heptane) to give the title compound. 1 H NMR (250 MHz, 353K DMSO-d6) δ 8.15 (d, J = 1.9 Hz, 1H), 7.65 (dd, J = 8.5, 2.4 Hz, 1H), 7.49 - 7.28 (m, 5H), 6.97 - 6.79 (m, 3H), 6.70 (s, 1H), 5.03 (s, 2H), 4.59 (s, 2H), 4.13 - 4.06 (m, 2H), 3.92 (s, 3H), 3.91 - 3.82 (m, 2H). Tr (METCR1410) = 1.18 min m / z (ES + ) (M+H) + 391.1.

[0359] (7-Hydroxy-3,5-dihydro-2H-1,4-benzoxazepin-4-yl)-(6-methoxy-3-pyridyl)methanone Pd / C (10%, 24 mg) was added to a stirred solution of (7-benzyloxy-3,5-dihydro-2H-1,4-benzoxazepin-4-yl)-(6-methoxy-3-pyridyl)methanone (220 mg, 0.56 mmol) in ethanol:THF (1:1, 20 mL). The reaction mixture was stirred under an atmosphere of hydrogen for 22 hours. The reaction mixture was filtered through Celite and washed with EtOH and EtOAc. The filtrate was concentrated in vacuo to give the title compound. 1 Tr (METCR1410) = 0.92 min m / z (ES + ) (M+H) + 301.1.

[0360] 7-[(5-methoxypyridin-2-yl)methoxy]-4-(6-methoxypyridine-3-carbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine To a solution of (7-hydroxy-3,5-dihydro-2H-1,4-benzoxazepin-4-yl)-(6-methoxy-3-pyridyl)methanone (90%, 180 mg, 0.54 mmol), potassium iodide (90 mg, 0.54 mmol), and cesium carbonate (356 mg, 1.08 mmol) in DMF (10 mL) was added a solution of 2-(chloromethyl)-5-methoxy-pyridine (102 mg, 0.65 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and partitioned between DCM (25 mL) and water (5 mL). The aqueous phase was washed with chloroform:isopropanol (3:1, 2 × 5 mL). The combined organics were dried (phase separator cartridge) and concentrated in vacuo. The crude residue was purified by column chromatography (silica, eluting with 0-100% EtOAc in heptane), and the relevant fractions were combined and concentrated in vacuo. The residue was dissolved in MeCN (0.5 mL) and water (1 mL) and lyophilized to dryness to give the title compound.

[0361] 1 H NMR (250 MHz, 353 K, DMSO-d6) δ 8.30 - 8.24 (m, 1H), 8.15 (d, J = 2.1 Hz, 1H), 7.65 (dd, J = 8.5, 2.4 Hz, 1H), 7.47 - 7.36 (m, 2H), 6.92 (d, J = 8.7 Hz, 1H), 6.89 - 6.80 (m, 2H), 6.70 (s, 1H), 5.03 (s, 2H), 4.59 (s, 2H), 4.14 - 4.04 (m, 2H), 3.92 (s, 3H), 3.91 - 3.82 (m, 5H). Tr (MET-uHPLC-AB-101) = 2.63 minutes, (ES + ) (M+H) + 422.

[0362] Method 26 Scheme of Method 26

[0363] [ka]

[0364] [Example 26] 2-[(5-methoxypyridin-2-yl)methoxy]-7-(6-methoxypyridine-3-carbonyl)-5,6,7,8-tetrahydro-1,7-naphthyridine tert-Butyl 2-hydroxy-5,6,7,8-tetrahydro-1,7-naphthyridine-7-carboxylate To a solution of 5,6,7,8-tetrahydro-1,7-naphthyridin-2-ol (500 mg, 3.16 mmol) in THF (15 mL) at 0° C. was added di-tert-butyl dicarbonate (759 mg, 3.48 mmol), followed by triethylamine (0.88 mL, 6.33 mmol). The reaction was stirred at room temperature for 16 hours. The reaction was quenched with water and extracted with EtOAc (3×20 mL). The combined organic layers were dried over NaSO, filtered, and evaporated under reduced pressure. The crude product was dissolved in EtOAc (10 mL), and the solution was allowed to stand at room temperature over the weekend. The material was filtered, washed with ether, and evaporated in vacuo at 40° C. for 3 hours to give the title compound. 1 H NMR (500 MHz, chloroform-d) δ 7.20 (d, J = 9.3 Hz, 1H), 6.45 (d, J = 9.2 Hz, 1H), 4.31 (s, 2H), 3.66 (t, J = 5.3 Hz, 2H), 2.75 (t, J = 5.5 Hz, 2H), 1.48 (s, 9H). Tr (METCR1410) = 0.91min m / z (ES + ) (M+H) + 251.

[0365] tert-Butyl 2-[(5-methoxypyridin-2-yl)methoxy]-5,6,7,8-tetrahydro-1,7-naphthyridine-7-carboxylate A mixture of tert-butyl 2-hydroxy-5,6,7,8-tetrahydro-1,7-naphthyridine-7-carboxylate (100 mg, 0.40 mmol), (5-methoxypyridin-2-yl)methanol (56 mg, 0.40 mmol), and CMBP (116 mg, 0.48 mmol) in toluene (3 mL) was stirred in a sealed tube at 100° C. for 3 hours. The reaction was cooled to room temperature, and the solvent was removed in vacuo. The residue was purified by low pH preparative HPLC to provide the title compound. 1 H NMR (500 MHz, chloroform-d) δ 8.31 (d, J = 2.9 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 8.6, 2.9 Hz, 1H), 6.67 Tr (METCR1673) = 1.16 min m / z (ES + ) (M+H) + 372.

[0366] tert-Butyl 1-[(5-methoxypyridin-2-yl)methyl]-2-oxo-1,2,5,6,7,8-hexahydro-1,7-naphthyridine-7-carboxylate Also isolated from the previous reaction as an off-white solid in 52 mg (35% yield). 1H NMR (500 MHz, chloroform-d) δ 8.19 (d, J = 2.9 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 7.14 (dd, J = 8.6, 2.9 Hz, 1H), 7.09 (d, J = 9.3 Hz, 1H), 6.55 (d, J = 9.3 Hz, 1H), 5.32 (s, 2H), 4.30 (s, 2H), 3.83 (s, 3H), 3.62 (s, 2H), 2.89 (t, J = 5.6 Hz, 2H), 1.47 (s, 9H). 1.03 min m / z (ES + ) (M+H) + 372.

[0367] 2-[(5-methoxypyridin-2-yl)methoxy]-7-(6-methoxypyridine-3-carbonyl)-5,6,7,8-tetrahydro-1,7-naphthyridine To a solution of tert-butyl 2-[(5-methoxypyridin-2-yl)methoxy]-5,6,7,8-tetrahydro-1,7-naphthyridine-7-carboxylate (58 mg, 0.16 mmol) in DCM (4 mL) was added TFA (0.48 mL, 6.25 mmol), and the reaction was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was purified by high pH preparative HPLC. Pure fractions were combined, and the solvent was removed in vacuo. The de-Boc product was dissolved in DMF (4 mL). To this solution was added 6-methoxypyridine-3-carboxylic acid (24 mg, 0.16 mmol), HATU (89 mg, 0.23 mmol), and DIPEA (101 mg, 0.78 mmol) at 0° C. The mixture was stirred at room temperature overnight. The solvent was removed in vacuo, and the crude product was purified by low pH preparative HPLC to give the title compound.

[0368] 1H NMR (500 MHz, DMSO-d6) δ 8.32 (d, J = 1.9 Hz, 1H), 8.29 (d, J = 2.6 Hz, 1H), 7.82 (d, J = 7.3 Hz, 1H), 7.66 - 7.44 (m, 3H), 6.89 (d, J = Tr (METCR1603) = 3.82 min m / z (ES + ) (M+H) + 407.

[0369] The following compounds were prepared similarly:

[0370] [Table 10]

[0371] Method 27 Scheme of Method 27

[0372] [ka]

[0373] [Example 27] 6-(5-methoxypyridin-2-yl)-3-[(5-methoxypyridin-2-yl)methoxy]-5,6,7,8-tetrahydro-1,6-naphthyridine 3-[(5-Methoxy-2-pyridyl)methoxy]-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride (50 mg, 0.16 mmol, prepared by Method 1), 2-bromo-5-methoxypyridine (46 mg, 0.24 mmol), sodium tert-butoxide (20 mg, 0.21 mmol), Pd(dba) (7 mg, 0.01 mmol), and BINAP (15 mg, 0.02 mmol) were suspended in tert-butanol (2 mL), and the mixture was heated in a microwave at 110 °C for 1 h. The reaction mixture was then dissolved in methanol and filtered. The precipitate was washed with water (1 mL) to give the title compound.

[0374] 1 H NMR (500 MHz, DMSO-d6) δ 8.29 (d, J = 2.9 Hz, 1H), 8.14 (d, J = 2.8 Hz, 1H), 7.89 (d, J = 3.0 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.43 (dd, J = 8.6, 2.9 Hz, 1H), 7.39 - 7.31 (m, 1H), 7.32 - 7.17 (m, 1H), 6.93 (d, J = 9.2 Hz, 1H), 5.15 (s, 2H), 4.60 (s, 2H), 3.84 (s, 3H), 3.80 (t, J = 6.0 Hz, 2H), 3.73 (s, 3H), 2.86 (t, J = 5.8 Hz, 2H). Tr (METCR1603) = 3.85 min, (ES + ) (M+H) + 379.

[0375] The following compounds were prepared similarly:

[0376] [Table 11]

[0377] Method 28 Method 28 scheme

[0378] [ka]

[0379] [Example 28] 2-[(5-methoxypyridin-2-yl)methoxy]-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)pyridine-4-carboxamide 7-Bromo-2-(6-methoxypyridine-3-carbonyl)-4-methyl-1,2,3,4-tetrahydroisoquinoline To a mixture of HATU (185 mg, 0.49 mmol), 6-methoxypyridine-3-carboxylic acid (230 mg, 1.50 mmol) in DMF (8 mL) was added DIPEA (0.78 mL, 4.50 mmol) at 0 °C. The reaction was stirred at room temperature for 30 minutes. 7-Bromo-4-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (433 mg, 1.65 mmol) was added. The reaction was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was suspended in water (30 mL) and the product was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude product was treated with DCM. The material was concentrated in vacuo, and the residue was purified by low pH preparative HPLC to provide the title compound. 1 H NMR (250 MHz, DMSO-d6) δ 8.28 (d, J = 1.8 Hz, 1H), 7.77 (dd, J = 8.5, 2.4 Hz, 1H), 7.38 (d, J = 7.4 Hz, 2H), 7.22 (d, J = 8.3 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 4.72 (q, J = 17.2 Hz, 2H), 3.93 (s, 3H), 3.71 (dd, J = 13.0, 4.6 Hz, 1H), 3.54 (dd, J = 13.0, 6.2 Hz, 1H), 1.19 (d, J = 6.9 Hz, 3H).Tr (METCR1410 2 min) = 1.2 min m / z (ES + ) (M+H) + 361 & 363.

[0380] 2-(6-Methoxypyridine-3-carbonyl)-4-methyl-1,2,3,4-tetrahydroisoquinolin-7-ol 7-Bromo-2-(6-methoxypyridine-3-carbonyl)-4-methyl-1,2,3,4-tetrahydroisoquinoline (420 mg, 1.16 mmol) was dissolved in THF (15 mL) and degassed with a stream of nitrogen for 5 minutes. Bis(pinacolato)diboron (325 mg, 1.28 mmol), KOAc (285 mg, 2.91 mmol), and PdCl(dppf) (85 mg, 0.12 mmol) were added, and the reaction was heated to 80 °C for 5 hours. The reaction was cooled to room temperature and quenched with water (50 mL). The aqueous phase was extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and evaporated under reduced pressure, and the residue was purified by column chromatography (silica, eluting with 0–60% EtOAc in heptane) to give the title compound. Tr (METCR1410) = 1.28 min m / z (ES + ) (M+H) + 409, 74%.

[0381] 2-(6-Methoxypyridine-3-carbonyl)-4-methyl-1,2,3,4-tetrahydroisoquinolin-7-ol To a solution of 2-(6-methoxypyridine-3-carbonyl)-4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (74%, 342 mg, 0.62 mmol) in THF (6 mL) and water (3 mL) was added NaBO3.4H2O (238 mg, 1.55 mmol). The reaction was stirred at room temperature for 3 h. The solvent was removed in vacuo, and the residue was diluted with NH4Cl (20 mL). The aqueous phase was extracted with DCM-MeOH (5:1, 3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by low pH preparative HPLC to give the title compound. 1H NMR (250 MHz, DMSO-d6) δ 8.26 (d, J = 1.9 Hz, 1H), 7.76 (dd, J = 8.5, 2.4 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 6.64 (dd, J = 8.3, 2.5 Hz, 1H), 6.53 (s, 1H), 4.73 - 4.49 (m, 2H), 3.93 (s, 3H), 3.69 (dd, J = 12.9, 4.6 Hz, 1H), 3.47 (dd, J = 12.8, 6.4 Hz, 1H), 1.15 (d, J = 6.9 Hz, 3H). Tr (METCR1410) = 0.98 min m / z (ES + ) (M+H) + 299.

[0382] 2-[(5-methoxypyridin-2-yl)methoxy]-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)pyridine-4-carboxamide A mixture of 2-(6-methoxypyridine-3-carbonyl)-4-methyl-1,2,3,4-tetrahydroisoquinolin-7-ol (140 mg, 0.47 mmol), (5-methoxypyridin-2-yl)methanol (72 mg, 0.52 mmol), and CMBP (136 mg, 0.56 mmol) in toluene (5 mL) was stirred at 100° C. in a sealed tube for 3 h. The reaction was cooled to room temperature, and the solvent was removed in vacuo. The residue was purified by low pH preparative HPLC followed by column chromatography (silica, eluting with 20-100% EtOAc in heptane) to give the title compound.

[0383] 1H NMR (250 MHz, 353 K, DMSO-d6) δ 8.27 (m, 2H), 7.77 (dd, J = 8.5, 2.4 Hz, 1H), 7.46 - 7.34 (m, 2H), 7.17 (d, J = 8.4 Hz, 1H), 6.92 - 6.80 (m, 3H), 5.07 (s, 2H), 4.78 - 4.54 (m, 2H), 3.93 (s, 3H), 3.85 (s, 3H), 3.71 (dd, J = 12.9, 4.6 Hz, 1H), 3.50 (dd, J = 12.9, 6.5 Hz, 1H), 3.00 - 2.88 (m, 1H), 1.17 (d, J = 6.9 Hz, 3H). Tr (METCR1603) = 4.3 min m / z (ES + ) (M+H) + 420, 100%.

[0384] Method 29 Method 29 scheme

[0385] [ka]

[0386] [Example 29] 7-[(5-methoxypyridin-2-yl)methoxy]-2-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinoline To a solution of 7-[(5-methoxy-2-pyridyl)methoxy]-1,2,3,4-tetrahydroisoquinoline hydrochloride (30 mg, 0.1 mmol, prepared by Method 1) in ethylene glycol (4 mL) was added copper(I) iodide (2 mg, 0.01 mmol), potassium phosphate (52 mg, 0.24 mmol), and 4-iodo-1-methyl-pyrazole (20 μL, 0.12 mmol). The reaction mixture was irradiated under nitrogen atmosphere under microwave conditions at 120° C. for 7 hours. After cooling to room temperature, the mixture was filtered and concentrated in vacuo. Water (5 mL) was added and extracted into DCM (5 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude residue was purified by basic preparative HPLC to give the title compound.

[0387] 1 H NMR (500 MHz, DMSO-d6) δ 8.28 (d, J = 2.3 Hz, 1H), 7.58 - 7.37 (m, 2H), 7.32 (s, 1H), 7.22 (s, 1H), 7.03 (d, J = 8.3 Hz, 1H), 6.92 - Tr (METCR1603) = 3.84 minutes, (ES + ) (M+H) + 351.

[0388] The following compounds were prepared similarly:

[0389] [Table 12]

[0390] method 30 Method 30 scheme

[0391] [ka]

[0392] [Example 30] 2-Methoxy-5-(3-{2-[(5-methoxypyridin-2-yl)oxy]ethyl}-3H,4H,5H,6H,7H-imidazo[4,5-c]pyridine-5-carbonyl)pyridine Benzyl 3H,4H,5H,6H,7H-imidazo[4,5-c]pyridine-5-carboxylate A mixture of 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine dihydrochloride (2.0 g, 10 mmol), NaHCO (2.4 g, 28 mmol), and N-(benzyloxycarbonyloxy)succinimide (2.5 g, 10 mmol) in dioxane / water (1:1, 80 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (20 mL) and brine (100 mL). The aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and evaporated under reduced pressure. This was purified by SCX column, washed with DCM (5 volumes), and the product was eluted with 10% (7M NH in MeOH) in DCM to give the title compound. 1 Tr (METCR1410) = 0.81 min m / z (ES + ) (M+H) + 258.

[0393] Benzyl 3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3H,4H,5H,6H,7H-imidazo[4,5-c]pyridine-5-carboxylate To a solution of benzyl 3H,4H,5H,6H,7H-imidazo[4,5-c]pyridine-5-carboxylate (1.5 g, 5.83 mmol) in DMF (30 mL) was added dropwise LiHMDS (1.0 M in THF / ethylbenzene, 7.0 mL, 7.0 mmol) at 0° C. The reaction was stirred at 0° C. for 30 minutes, (2-bromoethoxy)(tert-butyl)dimethylsilane (1.9 mL, 8.75 mmol) was added, and the reaction mixture was stirred at 0° C. for 0.5 hours and at room temperature overnight. The reaction was quenched with water (200 mL), and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, evaporated under reduced pressure, and the residue was purified by column chromatography (silica, eluting with 0-10% MeOH in DCM) to give the title compounds (a mixture of inseparable regioisomers). Tr (METCR1410) = 1.09 min m / z (ES + ) (M+H) + 416.

[0394] Benzyl 3-(2-hydroxyethyl)-3H,4H,5H,6H,7H-imidazo[4,5-c]pyridine-5-carboxylate To a solution of benzyl 3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3H,4H,5H,6H,7H-imidazo[4,5-c]pyridine-5-carboxylate (1.46 g, 3.34 mmol) in THF (20 mL) at 0° C. was added dropwise TBAF (1 M in THF, 4.34 mL, 4.34 mmol). The reaction was stirred at room temperature for 3 hours. The solvent was removed in vacuo. The residue was purified by high pH preparative HPLC to give the title compound (a mixture of inseparable regioisomers). Tr (METCR1410) = 0.79 min m / z (ES + ) (M+H) + 302.

[0395] Benzyl 3-{2-[(5-methoxypyridin-2-yl)oxy]ethyl}-3H,4H,5H,6H,7H-imidazo[4,5-c]pyridine-5-carboxylate A mixture of 2-fluoro-5-methoxypyridine (734 mg, 5.77 mmol), benzyl 3-(2-hydroxyethyl)-3H,4H,5H,6H,7H-imidazo[4,5-c]pyridine-5-carboxylate (870 mg, 2.88 mmol), and CsCO (2.35 g, 7.22 mmol) in DMSO (12 ml) was stirred in a sealed tube at 80 °C for 5 h. Additional CsCO (1.17 g, 3.61 mmol) was added, and the reaction was stirred at 80 °C for an additional 18 h. The reaction was cooled to room temperature, and the material was filtered. The crude product was purified by high pH preparative HPLC to give the title compound (a mixture of inseparable regioisomers). Tr (METCR1410) = 0.98 min m / z (ES + ) (M+H) + 409.

[0396] 2-(2-{3H,4H,5H,6H,7H-imidazo[4,5-c]pyridin-3-yl}ethoxy)-5-methoxypyridine To a solution of benzyl 3-{2-[(5-methoxypyridin-2-yl)oxy]ethyl}-3H,4H,5H,6H,7H-imidazo[4,5-c]pyridine-5-carboxylate (350 mg, 0.86 mmol) in EtOH (10 mL) was added Pd / C (91 mg, 0.09 mmol) at room temperature. The reaction was stirred overnight under a hydrogen atmosphere at room temperature. The reaction was filtered through a pad of Celite and washed thoroughly with MeOH. The filtrate was concentrated under reduced pressure, and the residue was purified by high-pH preparative HPLC to provide the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 7.82 (d, J = 3.1 Hz, 1H), 7.42 (s, 1H), 7.39 (dd, J = 9.0, 3.1 Hz, 1H), 6.75 (d, J = 9.0 Hz, 1H), 4.36 (t, J = 5.3 Tr (METCR1600) = 2.80 min m / z (ES +) (M+H) + 275.

[0397] 2-Methoxy-5-(3-{2-[(5-methoxypyridin-2-yl)oxy]ethyl}-3H,4H,5H,6H,7H-imidazo[4,5-c]pyridine-5-carbonyl)pyridine To a mixture of HATU (82 mg, 0.22 mmol) and 6-methoxypyridine-3-carboxylic acid (22 mg, 0.14 mmol) in DMF (3 mL) at 0° C. was added DIPEA (75 μL, 0.43 mmol). The reaction was stirred at room temperature for 30 minutes. 2-(2-{3H,4H,5H,6H,7H-imidazo[4,5-c]pyridin-3-yl}ethoxy)-5-methoxypyridine (39 mg, 0.14 mmol) was added, and the reaction was stirred at room temperature for 3 hours. The solvent was removed in vacuo, and the residue was purified by high pH preparative HPLC to provide the title compound.

[0398] 1 H NMR (250 MHz, 353 K, DMSO-d6) δ 8.29 (d, J = 2.1 Hz, 1H), 7.84 - 7.72 (m, 2H), 7.51 (s, 1H), 7.34 (dd, J = 8.9, 3.1 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 6.67 (d, J = 8.9 Hz, 1H), 4.69 (s, 2H), 4.43 (t, J = 5.2 Hz, 2H), 4.23 (t, J = 5.2 Hz, 2H), 3.93 (s, 3H), 3.78 (s, 3H), 3.71 (t, J = 5.7 Hz, 2H), 2.60 (t, J = 5.7 Hz, 2H). Tr (METCR1600) = 3.36 min m / z (ES + ) (M+H) + 410.

[0399] Method 31 Method 31 scheme

[0400] [ka]

[0401] [Example 31] 7-[(5-methoxypyridin-2-yl)methoxy]-2-(6-methoxypyridine-3-carbonyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline 7-(benzyloxy)-2-(6-methoxypyridine-3-carbonyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline To a mixture of HATU (745 mg, 1.96 mmol) and 6-methoxypyridine-3-carboxylic acid (200 mg, 1.31 mmol) in DMF (6 mL) was added DIPEA (680 μL, 3.92 mmol) at 0° C. The reaction was stirred at room temperature for 30 minutes. 7-(benzyloxy)-3-methyl-1,2,3,4-tetrahydroisoquinoline (347 mg, 1.37 mmol) was added. The reaction was stirred at room temperature overnight. The reaction was quenched with water (50 mL), and the aqueous phase was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated in vacuo, and the residue was purified by column chromatography (silica, eluting with 0–50% EtOAc in heptane) to give the title compound. 1 H NMR (250 MHz, DMSO-d6) δ 8.25 (dd, J = 2.4, 0.6 Hz, 1H), 7.75 (dd, J = 8.5, 2.4 Hz, 1H), 7.47 - 7.25 (m, 5H), 7.12 - 7.05 (m, 1H), 6.91 - 6.83 (m, 3H), 5.07 (s, 2H), 4.88 (d, J = 17.2 Hz, 1H), 4.59 - 4.44 (m, 1H), 4.36 (d, J = 17.4 Hz, 1H), 3.93 (s, 3H), 2.60 (d, J = 2.4 Hz, 1H), 1.12 (d, J = 6.7 Hz, 3H).Tr (METCR1410) = 1.27min m / z (ES + ) (M+H) + 389.

[0402] 2-(6-Methoxypyridine-3-carbonyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-ol To a solution of 7-(benzyloxy)-2-(6-methoxypyridine-3-carbonyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline (200 mg, 0.51 mmol) in EtOH (5 mL) was added Pd / C (10 mg, 0.10 mmol), and the reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction was filtered through a pad of Celite, and the material was washed thoroughly with MeOH. The filtrate was concentrated under reduced pressure to give the title compound. 1 H NMR (250 MHz, 353K, DMSO-d6) δ 8.24 (d, J = 2.4 Hz, 1H), 7.74 (dd, J = 8.5, 2.4 Hz, 1H), 6.95 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 6.63 (dd, J = 8.1, 2.5 Hz, 1H), 6.55 (s, 1H), 4.80 (d, J = 17.0 Hz, 1H), 4.49 (s, 1H), 4.30 (d, J = 17.2 Hz, 1H), 3.93 (s, 3H), 1.11 (d, J = 6.7 Hz, 3H).Tr (METCR1410) = 1.01 minutes, (ES + ) (M+H) + 299.

[0403] 7-[(5-methoxypyridin-2-yl)methoxy]-2-(6-methoxypyridine-3-carbonyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline A mixture of 2-(6-methoxypyridine-3-carbonyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-ol (145 mg, 0.49 mmol), (5-methoxypyridin-2-yl)methanol (74 mg, 0.54 mmol), and CMBP (141 mg, 0.58 mmol) in toluene (5 mL) was stirred in a sealed tube at 100° C. for 3 h. The reaction was cooled to room temperature, the solvent removed in vacuo, and the residue purified by low pH preparative HPLC followed by column chromatography (silica, eluting with 20-100% EtOAc in heptane) to give the title compound.

[0404] 1 H NMR (250 MHz, 353K, DMSO-d6) δ 8.25 (t, J = 2.4 Hz, 2H), 7.75 (dd, J = 8.5, 2.4 Hz, 1H), 7.49 - 7.34 (m, 2H), 7.08 (d, J = 9.1 Hz, 1H), 6.92 - 6.81 (m, 3H), 5.07 (s, 2H), 4.87 (d, J = 17.3 Hz, 1H), 4.52 (m, 1H), 4.36 (d, J = 17.3 Hz, 1H), 3.93 (s, 3H), 3.84 (s, 3H), 3.01 (m, 1H), 2.59 (m, 1H), 1.12 (d, J = 6.7 Hz, 3H). Tr (METCR1600) = 4.26 min m / z (ES + ) (M+H) + 420.2.

[0405] Method 32 Method 32 scheme

[0406] [ka]

[0407] [Example 32] 1-{7-[(5-hydroxypyridin-2-yl)methoxy]-1,2,3,4-tetrahydroisoquinolin-2-yl}ethan-1-one (5-Allyloxy-2-pyridyl)methanol 6-(Hydroxymethyl)pyridin-3-ol (5.0 g, 40 mmol) was suspended in acetone (80 mL) and a solution of potassium carbonate (7.7 g, 56 mmol) in 10 mL of water was added. The reaction mixture was heated to 60° C. for 1 h, and 3-bromoprop-1-ene (4.3 mL, 50 mmol) in acetone (20 mL) was added dropwise via addition funnel over 30 min, and the reaction was heated at 60° C. for an additional 2 h. The solution was cooled to room temperature and the pH was adjusted to approximately 7 with 6 M HCl. The volatiles were removed under reduced pressure, and the resulting solution was partitioned between EtOAc (50 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The combined organics were separated, dried over MgSO4, and concentrated under reduced pressure to provide the title compound. 1 H NMR (250 MHz, chloroform-d) δ 8.26 (d, J = 2.6 Hz, 1H), 7.25 - 7.20 (m, 1H), 7.17 (d, J = 8.5 Hz, 1H), 6.04 (ddt, J = 17.2, 10.5, 5.3 Hz, 1H), 5.53 - 5.24 (m, 2H), 4.70 (s, 2H), 4.59 (dt, J = 5.3, 1.4 Hz, 2H), 3.32 (s, 1H). Tr (METCR0990) = 1.29 min, (ES + ) (M+H) + 166.2, 100%.

[0408] 5-Allyloxy-2-(chloromethyl)pyridine To a solution of (5-allyloxy-2-pyridyl)methanol (0.50 g, 3.0 mmol) in DCM (40 mL) was added thionyl chloride (0.44 mL, 6.1 mmol) at 0° C., and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was co-distilled with DCM (3×20 mL) to give the title compound, which was used immediately in the next step without analysis.

[0409] tert-Butyl 7-[(5-allyloxy-2-pyridyl)methoxy]-3,4-dihydro-1H-isoquinoline-2-carboxylate tert-Butyl 7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (0.80 g, 3.2 mmol), KI (0.24 g, 1.5 mmol), and CsCO (2.1 g, 6.4 mmol) were dissolved in DMF (20 mL), and the reaction mixture was stirred at room temperature for 15 min. 5-Allyloxy-2-(chloromethyl)pyridine (549-4) (0.59 g, 3.2 mmol) was added, and the reaction mixture was stirred at room temperature overnight. DMF was removed under reduced pressure, and water (20 mL) was added to the reaction mixture, which was then extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated to give the crude product. The product was purified by column chromatography (silica, eluting with 0–20% EtOAc in heptane) to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 8.30 - 8.27 (m, 1H), 7.45 - 7.40 (m, 2H), 7.05 (d, J = 8.4 Hz, 1H), 6.86 - 6.79 (m, 2H), 6.09 - 5.99 (m, 1H), 5.44 - 5.38 (m, 1H), 5.28 (dd, J = 10.5, 1.4 Hz, 1H), 5.06 (s, 2H), 4.67 - 4.63 (m, 2H), 4.44 (s, 2H), 3.51 (t, J = 5.9 Hz, 2H), 2.68 (t, J = 5.8 Hz, 2H), 1.42 (s, 9H).

[0410] 7-[(5-Allyloxy-2-pyridyl)methoxy]-1,2,3,4-tetrahydroisoquinoline hydrochloride tert-Butyl 7-[(5-allyloxy-2-pyridyl)methoxy]-3,4-dihydro-1H-isoquinoline-2-carboxylate (0.30 g, 0.76 mmol) was suspended in 4 M HCl in dioxane (17 mL, 68 mmol), sonicated, and then stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 9.30 (s, 2H), 8.34 (d, J = 2.1 Hz, 1H), 7.57 - 7.48 (m, 2H), 7.14 (d, J = 8.4 Hz, 1H), 6.96 - 6.86 (m, 2H), 6.04 (ddt, J = 17.2, 10.5, 5.3 Hz, 1H), 5.46 - 5.36 (m, 1H), 5.30 (dd, J = 10.6, 1.5 Hz, 1H), 5.12 (s, 2H), 4.71 - 4.66 (m, 2H), 4.20 (t, J = 4.6 Hz, 2H), 3.36 - 3.30 (m, 2H), 2.92 (t, J = 6.2 Hz, 2H).

[0411] 1-[7-[(5-allyloxy-2-pyridyl)methoxy]-3,4-dihydro-1H-isoquinolin-2-yl]ethanone Acetic acid (0.054 g, 0.90 mmol) and HATU (0.34 mg, 0.90 mmol) were dissolved in DMF (25 mL) and DIPEA (0.24 mL, 1.4 mmol) was added. 7-[(5-Allyloxy-2-pyridyl)methoxy]-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.30 g, 0.90 mmol) was suspended in DMF (25 mL). DIPEA (0.24 mL, 1.4 mmol) was added and the reaction was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure, and the residue was dissolved in water (20 mL) and extracted into DCM (3 × 25 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (silica, eluting with 0-10% MeOH in DCM) followed by further column chromatography purification (silica, eluting with 50-100% EtOAc in heptane) to give the title compound.1 H NMR (500 MHz, DMSO-d6) δ 8.31 - 8.25 (m, 1H), 7.47 - 7.39 (m, 2H), 7.07 (d, J = 8.3 Hz, 1H), 6.87 - 6.80 (m, 2H), 6.10 - 5.98 (m, 1H), 5.46 - 5.38 (m, 1H), 5.29 (d, J = 10.5 Hz, 1H), 5.09 - 5.04 (m, 2H), 4.65 (d, J = 4.5 Hz, 2H), 4.56 (d, J = 23.8 Hz, 2H), 3.61 (t, J = 5.9Hz, 2H), 2.81 - 2.63 (m, 2H), 2.14 - 1.97 (m, 3H).

[0412] 1-{7-[(5-hydroxypyridin-2-yl)methoxy]-1,2,3,4-tetrahydroisoquinolin-2-yl}ethan-1-one A solution of 1-[7-[(5-allyloxy-2-pyridyl)methoxy]-3,4-dihydro-1H-isoquinolin-2-yl]ethanone (549-9) (0.20 g, 0.59 mmol) in DMF (20 mL) was degassed for 10 min. 1,3-Dimethylbarbituric acid (0.19 g, 1.2 mmol) and Pd(PPh3)4 (48 mg, 0.041 mmol) were added, and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, and the product was purified by column chromatography (silica, eluting with 50–100% EtOAc in heptane, followed by 0–5% MeOH in DCM). The resulting material was further purified by high-pH preparative HPLC followed by column chromatography (silica, eluting with 0–5% MeOH in DCM) to give the title compound.

[0413] 1H NMR (250 MHz, 353 K, DMSO-d6) δ 8.12 (d, J = 2.8 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.17 (dd, J = 8.4, 2.8 Hz, 1H), 7.07 (d, J = 8.3 Hz, Tr (MET-uHPLC-AB-101) = 1.59 min, (ES + ) (M+H) + 299.1.

[0414] Method 33 Method 33 scheme

[0415] [ka]

[0416] [Example 33] 2-Methylpropyl 7-[(5-methoxypyridin-2-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate To a solution of 7-[(5-methoxy-2-pyridyl)methoxy]-1,2,3,4-tetrahydroisoquinoline; hydrochloride (100 mg, 0.33 mmol, as prepared by Method 1) in DCM (10 mL) under a nitrogen atmosphere was added DIPEA (0.16 mL, 0.98 mmol), followed by 2-methylpropyl carbonochloridate (47 μL, 0.36 mmol). The reaction was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM (10 mL) and washed with 1 M HCl (20 mL). The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by basic preparative HPLC to give the title compound.

[0417] 1H NMR (250 MHz, 353 K, DMSO-d6) δ 8.45 - 8.04 (m, 1H), 7.72 - 7.25 (m, 2H), 7.07 (d, J = 8.1 Hz, 1H), 6.93 - 6.57 (m, 2H), 5.08 (s, 2H), 4.51 (s, 2H), 4.07 - 3.72 (m, 5H), 3.60 (t, J = 6.0 Hz, 2H), 2.74 (t, J = 6.0 Hz, 2H), 2.11 - 1.75 (m, 1H), 0.92 (d, J = 6.7 Hz, 6H). Tr (MET-uHPLC-AB-101) = 3.70 min, (ES + ) (M+H) + 371.

[0418] Method 34 Method 34 scheme

[0419] [ka]

[0420] [Example 34] (6-(2-fluoroethoxy)pyridin-3-yl)(7-((5-methoxypyridin-2-yl)methoxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone A mixture of 5-(7-((5-methoxypyridin-2-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyridin-2(1H)-one (0.200 g, 0.511 mmol, prepared by Method 1), 1-bromo-2-fluoroethane (0.078 g, 0.61 mmol), potassium carbonate (0.706 g, 5.11 mmol), and N,N-dimethylformamide (30.0 mL) was stirred at ambient temperature for 16 hours. After this time, ethyl acetate (20 mL) was added, and the mixture was washed with water (3 × 20 mL). The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by chromatography (silica gel; dichloromethane to 95:5 dichloromethane / methanol; gradient elution) to provide the title compound.

[0421] 1 H NMR (500 MHz, DMSO-d6) δ 8.30-8.27 (m, 2H), 7.84 (dd, J = 8.5, 2.0 Hz, 1H), 7.42 (br s, 2H), 7.08 (d, J = 8.5 Hz, 1H), 6.96-6.83 (m, 3H), 5.06 (br s, 2H), 4.82-4.81 (m, 1H), 4.73-4.59 (m, 4H), 4.54 (t, J = 4.0 Hz, 1H), 3.83-3.60 (m, 5H), 2.79 (t, J = 6.0 Hz, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -222.7; Tr (MET-AMRI001) = 12.83 min, (ESI) m / z 438 [M + H] + .

[0422] The following compounds were prepared similarly:

[0423] [Table 13]

[0424] Method 35 Method 35 scheme

[0425] [ka]

[0426] [Example 35] (7-((5-(allyloxy)pyridin-2-yl)methoxy)-3,4-dihydroisoquinolin-2(1H)-yl)(6-methoxypyridin-3-yl)methanone A mixture of 7-((5-(allyloxy)pyridin-2-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline trifluoroacetate (0.172 g, 0.580 mmol, prepared by Method 40) and 6-methoxynicotinic acid (0.089 g, 0.58 mmol) in dichloromethane (8.7 mL) was cooled to 0° C. and treated with pyridine (0.234 mL, 2.90 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.167 g, 0.871 mmol). The mixture was stirred at 0° C. for 10 minutes and at room temperature for 1 hour. After this time, the mixture was concentrated in vacuo. The resulting residue was purified by chromatography (silica gel; dichloromethane to 95:5 dichloromethane / methanol; gradient elution) to give the title compound: 1 H NMR (300 MHz, DMSO-d6) δ 8.32 (d, J = 1.8 Hz, 1H), 8.29 (s, 1H), 7.82 (dd, J = 8.7, 2.4 Hz, 1H), 7.43 (br s, 2H), 7.09 (d, J = 8.4 Hz, 1H), 6.92-6.83 (m, 3H), 6.11-5.98 (m, 1H), 5.41 (dd, J = 17.1, 1.5 Hz, 1H), 5.29 (dd, J = 10.5, 1.5 Hz, 1H), 5.05 (br s, 2H), 4.66-4.65 (m, 4H), 3.91 (s, 3H), 3.80-3.60 (m, 2H), 2.79 (t, J = 5.7 Hz, 2H); T r (MET-AMRI001) = 13.52 minutes, (ESI) m / z 432 [M + H] + .

[0427] Example 35.1 (7-((5-hydroxypyridin-2-yl)methoxy)-3,4-dihydroisoquinolin-2(1H)-yl)(6-methoxypyridin-3-yl)methanone 1,3-Dimethylbarbituric acid (0.124 g, 0.797 mmol) and tetrakis(triphenylphosphine)-palladium(0) (0.023 g, 0.020 mmol) were added to a solution of (7-((5-(allyloxy)pyridin-2-yl)methoxy)-3,4-dihydroisoquinolin-2(1H)-yl)(6-methoxypyridin-3-yl)methanone (0.172 g, 0.399 mmol) in methanol (14.4 mL), and the mixture was stirred at room temperature for 4.5 hours. After this time, the mixture was concentrated in vacuo. The resulting residue was combined with dichloromethane (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 × 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by chromatography (silica gel; dichloromethane to 95:5 dichloromethane / methanol; gradient elution). The product was lyophilized from acetonitrile (5 mL) and water (5 mL) to give the title compound.

[0428] 1 H NMR (500 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.31 (d, J = 2.0 Hz, 1H), 8.10 (br s, 1H), 7.81 (dd, J = 8.5, 2.0 Hz, 1H), 7.31 (br s, 1H), 7.17 (d, J = 6.5 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.90-6.82 (m, 3H), 5.00 (br s, 2H), 4.67 (br s, 2H), 3.91 (s, 3H), 3.76-3.60 (m, 2H), 2.79 (t, J = 5.5 Hz, 2H); T r (MET-AMRI-001) = 11.62 minutes, (ESI) m / z 392 [M + H] + .

[0429] method 36 Method 36 scheme

[0430] [ka]

[0431] [Example 36] (6-(fluoromethoxy)pyridin-3-yl)(7-((5-methoxypyridin-2-yl)methoxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone Methyl 6-(fluoromethoxy)nicotinate A mixture of methyl 6-oxo-1,6-dihydropyridine-3-carboxylate (0.200 g, 1.30 mmol), fluoromethyl 4-methylbenzenesulfonate (0.400 g, 1.96 mmol), and potassium carbonate (1.81 g, 13.1 mmol) in N,N-dimethylformamide (4.9 mL) was stirred at 50° C. for 16 hours. After this time, ethyl acetate (20 mL) was added, and the mixture was washed with water (3×20 mL). The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by chromatography (silica gel; dichloromethane to 95:5 dichloromethane / methanol; gradient elution) to give the title compound: 1 H NMR (300 MHz, DMSO-d6) δ 8.81 (dd, J = 2.4, 0.6 Hz, 1H), 8.32 (dd, J = 8.4, 2.4 Hz, 1H), 7.13 (dd, J = 8.4, 0.6 Hz, 1H), 6.15 (d, J = 52.2 Hz, 2H), 3.87 (s, 3H).

[0432] 6-(Fluoromethoxy)nicotinic acid A solution of methyl 6-(fluoromethoxy)nicotinate (0.082 g, 0.44 mmol) in tetrahydrofuran (3.7 mL) was treated with a solution of lithium hydroxide monohydrate (0.019 g, 0.44 mmol) in water (3.7 mL), and the mixture was stirred at ambient temperature for 1 hour. After this time, volatiles were removed in vacuo, and water (40 mL) was added. The aqueous mixture was washed with dichloromethane (3 x 75 mL), and the pH was adjusted to 3 with 2.0 N hydrochloric acid, which was added dropwise. The resulting solid was collected by filtration, washed with water (20 mL), and evaporated to dryness in vacuo to give a first crop of the title compound, 0.031 g (41%). The filtrate was extracted with dichloromethane (3 x 10 mL), and the combined organic layers were concentrated in vacuo to give a second crop of the title compound: 1 H NMR (300 MHz, DMSO-d6) δ 13.30 (br s, 1H), 8.78-8.77 (m, 1H), 8.28 (dd, J = 8.4, 2.4 Hz, 1H), 7.11-7.08 (m, 1H), 6.14 (d, J = 52.2 Hz, 2H).

[0433] (6-(fluoromethoxy)pyridin-3-yl)(7-((5-methoxypyridin-2-yl)methoxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone Pyridine (0.060 mL, 0.74 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.043 g, 0.22 mmol) were added to a mixture of 7-((5-methoxypyridin-2-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline (0.040 g, 0.15 mmol, prepared by Method 1) and 6-(fluoromethoxy)-nicotinic acid (0.035 g, 0.21 mmol) in dichloromethane (4.0 mL) at 0° C., and the mixture was stirred at 0° C. for 10 minutes and at ambient temperature for 16 hours. After this time, the solvent was removed in vacuo. The resulting residue was purified by chromatography (silica gel; dichloromethane to 95:5 dichloromethane / methanol; gradient elution) to provide the title compound.

[0434] 1H NMR (300 MHz, DMSO-d6) δ 8.38 (d, J = 1.8 Hz, 1H), 8.28 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.42 (br s, 2H), 7.10-7.07 (m, 2H), 6.96-6.83 (m, 2H), 6.13 (d, J = 52.5 Hz, 2H), 5.08 (br s, 2H), 4.72-4.61 (m, 2H), 3.83-3.57 (m, 5H), 2.79 (br s, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -154.7; T r (MET-AMRI001) = 12.91 min, (ESI) m / z 424 [M + H] + .

[0435] Method 37 Method 37 scheme

[0436] [ka]

[0437] [Example 37] (7-((5-(fluoromethoxy)pyridin-2-yl)methoxy)-3,4-dihydroisoquinolin-2(1H)-yl)(6-methoxypyridin-3-yl)methanone tert-Butyl 7-((5-(fluoromethoxy)pyridin-2-yl)methoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate A mixture of tert-butyl 7-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.136 g, 0.547 mmol), (5-(fluoromethoxy)pyridin-2-yl)methanol (0.043 g, 0.28 mmol) and toluene (5.8 mL) was treated with (tributylphosphoranylidene)acetonitrile (0.165 g, 0.684 mmol) and the mixture was heated at 100° C. for 16 hours. After this time, the solvent was removed in vacuo and the resulting residue was purified by chromatography (silica gel; dichloromethane to 95:5 dichloromethane / methanol; gradient elution) to provide the title compound: 1 H NMR (300 MHz, DMSO-d6) δ 8.42 (d, J = 3.0 Hz, 1H), 7.62 (dd, J = 8.4, 2.7 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.86-6.80 (m, 2H), 5.93 (d, J = 53.7 Hz, 2H), 5.11 (s, 2H), 4.45 (s, 2H), 3.52 (t, J = 6.0 Hz, 2H), 2.68 (t, J = 6.0 Hz, 2H), 1.42 (s, 9H).

[0438] 7-((5-(fluoromethoxy)pyridin-2-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline A solution of tert-butyl 7-((5-(fluoromethoxy)pyridin-2-yl)methoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.037 g, 0.095 mmol) in dichloromethane (0.3 mL) was treated with trifluoroacetic acid (0.37 mL, 4.9 mmol), and the mixture was stirred at room temperature for 3 hours. After this time, the solvent was removed in vacuo, and the resulting residue was dissolved in dichloromethane (10 mL) and washed with saturated aqueous sodium bicarbonate (20 mL). The aqueous layer was extracted with dichloromethane (10 mL). The combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to provide the title compound, which was used directly in the next step.

[0439] (7-((5-(fluoromethoxy)pyridin-2-yl)methoxy)-3,4-dihydroisoquinolin-2(1H)-yl)(6-methoxypyridin-3-yl)methanone Pyridine (0.038 mL, 5.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.027 g, 0.14 mmol) were added to a mixture of 7-((5-(fluoromethoxy)-pyridin-2-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline (0.027 g, 0.094 mmol) and 6-methoxynicotinic acid (0.020 g, 0.13 mmol) in dichloromethane (2.5 mL) at 0° C., and the mixture was stirred at 0° C. for 10 minutes and at ambient temperature for 16 hours. After this time, the solvent was removed in vacuo. The resulting residue was purified by chromatography (silica gel; dichloromethane to 95:5 dichloromethane / methanol; gradient elution) to provide the title compound.

[0440] 1 H NMR (500 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.31 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 8.5, 2.0 Hz, 1H), 7.61 (d, J = 6.5 Hz, 1H), 7.53 (br s, 1H), 7.09 (d, J = 8.5 Hz, 1H), 6.94-6.84 (m, 3H), 5.92 (d, J = 53.5 Hz, 2H), 5.11 (br s, 2H), 4.68 (br s, 2H), 3.91-3.59 (m, 5H), 2.79 (t, J = 5.5 Hz, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -151.4; T r (MET-AMRI001) = 13.93 min, MS (ESI) m / z 424 [M + H] + .

[0441] Method 38 Method 38 scheme

[0442] [ka]

[0443] [Example 38] (7-((5-(2-fluoroethoxy)pyridin-2-yl)methoxy)-3,4-dihydroisoquinolin-2(1H)-yl)(6-methoxypyridin-3-yl)methanone (5-(2-fluoroethoxy)pyridin-2-yl)methanol A mixture of 6-(hydroxymethyl)pyridin-3-ol (0.250 g, 2.00 mmol), 1-bromo-2-fluoroethane (0.304 g, 2.40 mmol), potassium carbonate (2.76 g, 20.0 mmol), and N,N-dimethylformamide (15.6 mL) was stirred at ambient temperature for 16 hours. After this time, ethyl acetate (20 mL) was added, and the mixture was washed with water (3 × 20 mL). The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by chromatography (silica gel; dichloromethane to 95:5 dichloromethane / methanol; gradient elution) to give the title compound: 1 H NMR (300 MHz, DMSO-d6) δ 8.22 (d, J = 2.1 Hz, 1H), 7.45-7.37 (m, 2H), 5.31 (t, J = 6.0 Hz, 1H), 4.86-4.82 (m, 1H), 4.69-4.66 (m, 1H), 4.49 (d, J = 5.7 Hz, 2H), 4.37-4.34 (m, 1H), 4.27-4.24 (m, 1H).

[0444] tert-Butyl 7-((5-(2-fluoroethoxy)pyridin-2-yl)methoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate A mixture of tert-butyl 7-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.318 g, 1.27 mmol) and (5-(2-fluoroethoxy)pyridin-2-yl)methanol (0.109 g, 0.637 mmol) in toluene (22.2 mL) was treated with (tributylphosphoranylidene)acetonitrile (0.384 g, 1.59 mmol) and the mixture was heated at 100° C. for 3 hours. After this time, the mixture was concentrated in vacuo. The resulting residue was purified by chromatography (silica gel; dichloromethane to 95:5 dichloromethane / methanol; gradient elution) to give the title compound: 1 H NMR (300 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.45 (d, J = 1.5 Hz, 2H), 7.06 (d, J = 8.4 Hz, 1H), 6.84-6.81 (m, 2H), 5.07 (s, 2H), 4.84 (t, J = 3.9 Hz, 1H), 4.68 (t, J = 3.9 Hz, 1H), 4.48-4.37 (m, 3H), 4.28 (t, J = 3.9 Hz, 1H), 3.52 (t, J = 5.7 Hz, 2H), 2.68 (t, J = 5.4 Hz, 2H), 1.42 (s, 9H).

[0445] 7-((5-(2-fluoroethoxy)pyridin-2-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline trifluoroacetate A mixture of tert-butyl 7-((5-(2-fluoroethoxy)pyridin-2-yl)methoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.135 g, 0.335 mmol) in methylene chloride (1.3 mL) was treated with trifluoroacetic acid (1.31 mL, 17.1 mmol) and the mixture was stirred at ambient temperature for 1 hour. After this time, the mixture was concentrated in vacuo to provide the title compound: MS (ESI) m / z 303 [M + H] + .

[0446] (7-((5-(2-fluoroethoxy)pyridin-2-yl)methoxy)-3,4-dihydroisoquinolin-2(1H)-yl)(6-methoxypyridin-3-yl)methanone Pyridine (0.133 mL, 1.65 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.095 g, 0.50 mmol) were added to a mixture of 7-((5-(2-fluoroethoxy)-pyridin-2-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline trifluoroacetate (0.100 g, 0.240 mmol) and 6-methoxynicotinic acid (0.051 g, 0.33 mmol) in dichloromethane (5.0 mL) at 0° C., and the mixture was stirred at 0° C. for 10 minutes and at ambient temperature for 16 hours. After this time, the mixture was concentrated in vacuo. The resulting residue was purified by chromatography (silica gel; dichloromethane to 95:5 methylene chloride / methanol; gradient elution). The product was lyophilized from acetonitrile (5 mL) and water (5 mL) to give the title compound.

[0447] 1 H NMR (500 MHz, DMSO-d6) δ 8.31 (d, J = 1.5 Hz, 2H), 7.81 (dd, J = 8.5, 2.0 Hz, 1H), 7.45 (s, 2H), 7.08 (d, J = 8.5 Hz, 1H), 6.93-6.83 (m, 3H), 5.07 (br s, 2H), 4.80 (t, J = 4.0 Hz, 1H), 4.72-4.67 (m, 3H), 4.36 (t, J = 4.0 Hz, 1H), 4.30 (t, J = 4.0 Hz, 1H), 4.29 (s, 3H), 3.91-3.60 (m, 2H), 2.79 (t, J = 5.5 Hz, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -222.3; T r (MET-AMRI001) = 12.87 min, MS (ESI) m / z 438 [M + H] + .

[0448] Method 39 Method 39 scheme

[0449] [ka]

[0450] [Example 39] 5-(7-((5-methoxypyridin-2-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyridin-2(1H)-one 2-(chloromethyl)-5-methoxypyridine A solution of (5-methoxypyridin-2-yl)methanol (0.100 g, 0.719 mmol) in dichloromethane (5.0 mL) was treated with thionyl chloride (0.105 mL, 1.44 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 hour. After this time, the solution was poured into water (10 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2×25 mL). The organic layers were combined, dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give the title compound: 1 H NMR (300 MHz, CDCl3) δ 8.28-8.27 (m, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.21 (dd, J = 8.7, 3.0 Hz, 1H), 4.65 (s, 2H), 3.87 (s, 3H).

[0451] tert-Butyl 7-((5-methoxypyridin-2-yl)methoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate A solution of tert-butyl 7-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.830 g, 3.33 mmol) in N,N-dimethylformamide (24.2 mL) was treated with cesium carbonate (5.42 g, 16.6 mmol), 2-(chloromethyl)-5-methoxypyridine (0.682 g, 4.33 mmol), and potassium iodide (0.055 g, 0.33 mmol), and the mixture was stirred at ambient temperature for 16 hours. After this time, the solution was diluted with ethyl acetate (100 mL) and washed with water (3 × 100 mL). The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by chromatography (silica gel; dichloromethane to 95:5 dichloromethane / methanol; gradient elution) to give the title compound: 1 H NMR (300 MHz, CDCl3) δ 8.29 (d, J = 2.7 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.22 (dd, J = 8.7, 3.0 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.81 (dd, J = 8.4, 2.4 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H), 5.12 (s, 2H), 4.52 (s, 2H), 3.87 (s, 3H), 3.62 (br s, 2H), 2.77-2.74 (m, 2H), 1.49 (s, 9H).

[0452] 7-((5-methoxypyridin-2-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline trifluoroacetate A solution of tert-butyl 7-((5-methoxypyridin-2-yl)methoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.500 g, 1.35 mmol) in dichloromethane (5.3 mL) was treated with trifluoroacetic acid (5.29 mL, 68.7 mmol) and the mixture was stirred at ambient temperature for 1 hour. After this time, the solution was concentrated in vacuo to provide the title compound, which was used without further purification.

[0453] 5-(7-((5-methoxypyridin-2-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyridin-2(1H)-one A solution of 7-((5-methoxypyridin-2-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline trifluoroacetate (0.365 g, 1.35 mmol) in dichloromethane (20.3 mL) was treated with 6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.188 g, 1.35 mmol) at 0° C., followed by pyridine (0.544 mL, 6.75 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.388 g, 2.03 mmol). The solution was stirred at 0° C. for 10 minutes and at ambient temperature for 1 hour. After this time, the solution was concentrated in vacuo, and the resulting residue was purified by chromatography (silica gel; dichloromethane to 95:5 dichloromethane / methanol; gradient elution) to provide the title compound.

[0454] 1 H NMR (500 MHz, CDCl3) δ 12.22 (br s, 1H), 8.29 (d, J = 3.0 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H), 7.61 (dd, J = 9.5, 2.5 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.22 (dd, J = 8.0, 2.0 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 6.85 (dd, J = 8.5, 2.5 Hz, 1H), 6.72 (br s, 1H), 6.61 (d, J = 9.5 Hz, 1H), 5.12 (s, 2H), 4.70 (s, 2H), 3.04 (s, 3H), 3.79 (br s, 2H), 2.87 (t, J = 5.5 Hz, 2H); T r (MET-AMRI001) = 10.32, (ESI) m / z 392 [M + H] + .

[0455] method 40 Method 40 scheme

[0456] [ka]

[0457] [Example 40] 5-(7-((5-hydroxypyridin-2-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylpyridin-2(1H)-one (5-(allyloxy)pyridin-2-yl)methanol A solution of 6-(hydroxymethyl)pyridin-3-ol (0.100 g, 0.799 mmol) and allyl bromide (0.080 mL, 0.92 mmol) in acetone (3.0 mL) was treated dropwise with a solution of potassium carbonate (0.166 g, 1.19 mmol) in water (3.0 mL), and the solution was heated at 60° C. for 2 hours. After this time, the solution was cooled to ambient temperature and extracted with tert-butyl methyl ether (3×40 mL). The combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to provide the title compound: 1 H NMR (300 MHz, CDCl3) δ 8.27 (d, J = 2.4 Hz, 1H), 7.25-7.16 (m, 2H), 6.11-5.98 (m, 1H), 5.47-5.45 (m, 1H), 5.41-5.30 (m, 1H), 4.70 (s, 2H), 4.61-4.58 (m, 2H), 3.39 (br s, 1H).

[0458] tert-Butyl 7-((5-(allyloxy)pyridin-2-yl)methoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate A solution of tert-butyl 7-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.815 g, 3.27 mmol) and (5-(allyloxy)pyridin-2-yl)methanol (0.270 g, 1.63 mmol) in toluene (57.0 mL) was treated with (tributylphosphoranylidene)acetonitrile (0.986 g, 4.09 mmol) and the mixture was heated at 100° C. for 3 hours. After this time, the solution was concentrated in vacuo and the resulting residue was purified by chromatography (silica gel; dichloromethane to 95:5 dichloromethane / methanol; gradient elution) to provide the title compound: 1 H NMR (300 MHz, CDCl3) δ 8.30 (d, J = 2.7 Hz, 1H), 7.41 (d, J = 8.7 Hz, 1H), 7.23 (dd, J = 8.4, 2.7 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.81 (dd, J = 8.4, 2.4 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H), 6.11-5.98 (m, 1H), 5.47-5.40 (m, 1H), 5.36-5.31 (m, 1H), 5.12 (s, 2H), 4.59 (dt, J = 3.6, 1.5 Hz, 2H), 4.52 (br s, 2H), 3.62 (t, J = 5.1 Hz, 2H), 2.75 (t, J = 5.7 Hz, 2H), 1.49 (s, 9H).

[0459] 7-((5-(allyloxy)pyridin-2-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline trifluoroacetate A solution of tert-butyl 7-((5-(allyloxy)pyridin-2-yl)methoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.270 g, 0.681 mmol) in dichloromethane (2.7 mL) was treated with trifluoroacetic acid (2.67 mL, 34.7 mmol) and the mixture was stirred at ambient temperature for 1 hour. After this time, the solution was concentrated in vacuo to provide the title compound, which was used without further purification.

[0460] 5-(7-((5-(allyloxy)pyridin-2-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylpyridin-2(1H)-one A solution of 7-((5-(allyloxy)pyridin-2-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline trifluoroacetate (0.177 g, 0.597 mmol) in dichloromethane (9.0 mL) was treated with 1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.091 g, 0.59 mmol) at 0° C., followed by pyridine (0.241 mL, 2.99 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.172 g, 0.896 mmol). The suspension was stirred at 0° C. for 10 minutes and at ambient temperature for 1 hour. After this time, the solvent was removed in vacuo, and the resulting residue was purified by chromatography (silica gel; dichloromethane to 95:5 dichloromethane / methanol; gradient elution) to give the title compound: 1 H NMR (300 MHz, CDCl3) δ 8.31 (d, J = 2.7 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.46-7.39 (m, 2H), 7.23 (dd, J = 8.4, 2.7 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.85 (dd, J = 8.4, 2.7 Hz, 1H), 6.72 (br s, 1H), 6.57 (d, J = 9.3 Hz, 1H), 6.11-5.98 (m, 1H), 5.47-5.40 (m, 1H), 5.36-5.30 (m, 1H), 5.11 (s, 2H), 4.69 (br s, 2H), 4.59 (dt, J = 3.9, 1.5 Hz, 2H), 3.78 (t, J = 5.4 Hz, 2H), 3.58 (s, 3H), 2.88 (t, J = 6.0 Hz, 2H).

[0461] 5-(7-((5-hydroxypyridin-2-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylpyridin-2(1H)-one A suspension of 5-(7-((5-(allyloxy)pyridin-2-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylpyridin-2(1H)-one (0.225 g, 0.521 mmol) in methanol (18.8 mL) was treated with 1,3-dimethylbarbituric acid (0.163 g, 1.04 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.030 g, 0.026 mmol), and the mixture was stirred at ambient temperature for 4.5 hours. After this time, the solution was concentrated in vacuo, and the resulting residue was diluted with dichloromethane (20 mL). The solution was washed with saturated aqueous sodium bicarbonate (20 mL), and the aqueous layer was extracted with dichloromethane (2 × 30 mL). The combined organic solution was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by chromatography (silica gel; dichloromethane to 95:5 dichloromethane / methanol; gradient elution). The product was lyophilized from acetonitrile (5 mL) and water (5 mL) to give the title compound.

[0462] 1 H NMR (500 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.10 (d, J = 2.5 Hz, 1H), 8.04 (d, J = 2.5 Hz, 1H), 7.53 (dd, J = 9.5, 5.5 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.17 (dd, J = 8.5, 3.0 Hz, 1H), 7.08 (d, J = 8.5 Hz, 1H), 6.87 (s, 1H), 6.83 (dd, J = 8.5, 3.0 Hz, 1H), 6.41 (d, J = 9.5 Hz, 1H), 5.00 (s, 2H), 4.65 (s, 2H), 3.69 (t, J = 6.0 Hz, 2H), 3.46 (s, 3H), 2.79 (t, J = 5.5 Hz, 2H); T r = (MET-AMRI001) = 10.06 min, (ESI) m / z 392 [M + H] + .

[0463] Method 41 Method 41 scheme

[0464] [ka]

[0465] [Example 41] 5-(7-((5-methoxypyridin-2-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylpyridin-2(1H)-one A mixture of 5-(7-((5-hydroxypyridin-2-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylpyridin-2(1H)-one (0.094 g, 0.24 mmol, prepared by Method 40) and potassium carbonate (0.332 g, 2.40 mmol) in N,N-dimethylformamide (14.1 mL) was treated with methyl 4-nitrobenzenesulfonate (0.063 g, 0.29 mmol), and the mixture was stirred at ambient temperature for 16 hours. After this time, the mixture was diluted with ethyl acetate (20 mL) and washed with water (3 × 50 mL). The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by chromatography (silica gel; dichloromethane to 95:5 dichloromethane / methanol; gradient elution). The product was lyophilized from acetonitrile (5 mL) and water (5 mL) to give the title compound.

[0466] 1H NMR (500 MHz, DMSO-d6) δ 8.27 (d, J = 2.5 Hz, 1H), 8.04 (d, J = 2.5 Hz, 1H), 7.53 (dd, J = 9.0, 2.5 Hz, 1H), 7.45-7.40 (m, 2H), 7.08 (d, J = 8.5 Hz, 1H), 6.88 (s, 1H), 6.84 (dd, J = 8.5, 2.5 Hz, 1H), 6.41 (d, J = 9.0 Hz, 1H), 5.06 (s, 2H), 4.65 (s, 2H), 3.83 (s, 3H), 3.69 (t, J = 5.5 Hz, 2H), 3.47 (s, 3H), 2.79 (t, J = 5.5 Hz, 2H); T r (MET-AMRI001) = 10.53, (ESI) m / z 406 [M + H] + .

[0467] Biotechnology Q46 radioactive リガンド combined with アッセイ For radioligand binding assays (RBA), MBP-HTT(1-89)Q46-His(6x) ("Exon1-Q46") protein was prepared based on a previous publication (Scherzinger et al., Cell, Vol. 90, pp. 549-558, August 8, 1997). For the experiments, 30 μM MBP-Exon1-Q46 was incubated with 150 μg / mL thrombin and 2 mM CaCl2 in assay buffer (150 mM NaCl, 50 mM Tris, pH 8.0) at 37°C for 16 h. Aggregated Exon1-Q46 was pelleted by centrifugation at 13,000 rpm for 5 min in a tabletop centrifuge and redissolved in an equal volume of assay buffer. Test compounds were prepared at 11 concentrations ranging from 63 μM to 2 nM by titration in DMSO. For RBA, Q46 protein aggregates and test compounds were pre-incubated in assay buffer at 100 μL / well in a 96-well plate (pp, round bottom) for 20 min at room temperature. Ligand was then added at 50 μL / well and incubated at 37°C for 60 min. Final assay concentrations were 1 μM to 30 pM test compound, 1 μM Exon1-Q46 protein (equivalent monomer concentration), and 0.3 nM ligand [ 3 The antibody was [H3-methyl]-5-((5-methoxypyridin-2-yl)methoxy)-2-(pyrazin-2-yl)benzo[d]oxazole. Samples were transferred onto GF / B filter plates and washed twice with PBS (200 μL) using a Filtermate harvester. After drying the filter plates at 55°C for 1 hour, the plates were sealed under foil and 30 μL / well of scintillation fluid (Packard MicroScint 40) was added, incubated for 15 minutes in the dark, and counted on a MicroBeta reader. For analysis, replicate data from independent assay plates were compared against vehicle control wells (0% inhibition) and 1 μM unlabeled [ 3 H3-methyl]-5-((5-methoxypyridin-2-yl)methoxy)-2-(pyrazin-2-yl)benzo[d]oxazole (100% inhibition) was used to normalize to 0% inhibition and 100% inhibition. IC 50Values were calculated using normalized replicate data and four variables (top, bottom, slope, IC) in the overall fit. 50 ) was determined using the S-order inhibition model. The results for various example compounds are shown in the table below:

[0468] [Table 14] TIFF0007720847000089.tif246135TIFF0007720847000090.tif246133TIFF0007720847000091.tif119145

[0469] 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.

[0470] The invention illustratively described herein can suitably be practiced in the absence of any element or elements, or limitation or limitations, not specifically disclosed herein. Thus, for example, terms such as "comprising," "including," and "containing" should be interpreted openly and without limitation. Furthermore, the terms and expressions used herein are used as terms of description rather than limitation, and there is no intention in the use of such terms and expressions to exclude equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention as defined in the claims.

[0471] Thus, while the present invention has been specifically disclosed in terms of preferred embodiments, it should be understood that those skilled in the art may employ any of the features, modifications, improvements, and variations of the invention disclosed and practiced herein, and that such modifications, improvements, and variations are considered to be within the scope of the present invention. The materials, methods, and examples presented herein are exemplary and representative of preferred embodiments, and are not intended to limit the scope of the invention.

[0472] The present invention has been broadly and generically described herein. Each of the narrower chemical species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes generic descriptions of the invention with a provisio or negative limitation excluding any subject matter from the genus, regardless of whether the excluded material is specifically recited.

[0473] Furthermore, when features or aspects of the invention are described in terms of a Markush group, those skilled in the art will recognize that the invention is also thereby described with respect to any individual member or subgroup of members of the Markush group.

[0474] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, as if each were individually incorporated by reference. In case of conflict, the present specification, including definitions, will control.

[0475] While the present invention has been described in conjunction with the above embodiments, it is understood that the foregoing descriptions and examples are intended to be illustrative and not to limit the scope of the invention. Other aspects, advantages and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains. The following is one embodiment of the present invention. (1) Formula (I): [ka] [In the formula, Z 1 and Z 2 are each independently CH, or Z 1 and Z 2 one of which is N and the other is CH; Z 3 is N or CH; L 1 -OC1~4 Alkylene, -OC 1~4 Alkylene-O- or -N(R 4 )C(=O)-; X 1 and X 2 One of them is NL 2 -R 2 and the other is CH 2 and; X 3 is CH 2 or -O-CH 2 - and; L 2 is -(CH 2 ) n -, -C(=O)-, -C(=O)NH-, -C(=O)(O)-(CH 2 ) n , or -S(=O) 2 and; n is 0, 1, or 2; R 1 are aryl or heteroaryl, and are halogen, haloalkyl, hydroxy, alkyl, alkoxy, haloalkoxy, and —N(R 4 ) 2 optionally substituted with 1 or 2 substituents independently selected from: R 2 is aryl, alkyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl, each of which is selected from the group consisting of alkyl optionally substituted with halogen, haloalkyl, hydroxy, alkenyl, or alkoxy, alkoxy optionally substituted with alkenyl or alkoxy, haloalkoxy, heteroaryl, and —N(R 4 ) 2 optionally substituted with 1 or 2 substituents independently selected from: p is 0, 1 or 2; Each R 3 is independently C 1~4 alkyl, or two R on the same carbon 3 forms an oxo, where R 3 teeth,

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Claims

1. Formula (I): 【Chemical 1】 [In the formula, Z 1 and Z 2 are each independently CH, or Z 1 and Z 2 one of which is N and the other is CH; Z 3 is N or CH; L 1 -OC 1～4 is alkylene; X 1 and X 2 One of them is NL 2 -R 2 and the other is CH 2 and; X 3 is CH 2 or -O-CH 2 - and; L 2 is -(CH 2 ) n -, -C(=O)-, -C(=O)NH-, -C(=O)(O)-(CH 2 ) n , or -S(=O) 2 and; n is 0, 1, or 2; R 1 is pyridinyl optionally substituted with methoxy; R 2 is aryl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl, each of which is selected from the group consisting of halogen, haloalkyl, hydroxy, alkyl optionally substituted with alkenyl or alkoxy, alkoxy optionally substituted with alkenyl or alkoxy, haloalkoxy, heteroaryl, and —N(R 4 ) 2 optionally substituted with 1 or 2 substituents independently selected from: p is 0, 1 or 2; Each R 3 is independently C 1～4 alkyl, or two R on the same carbon 3 forms an oxo, where R 3 teeth, 【Chemistry 2】 one or more ring carbon atoms of which may be substituted; Each R 4 are independently H or C 1-4 alkyl] or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers thereof.

2. Formula (IIa): 【Chemistry 3】 or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers thereof.

3. Formula (IIb): 【Chemistry 4】 or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers thereof.

4. Formula (IIIa): 【Chemistry 5】 or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers thereof.

5. Formula (IIIb): 【Chemistry 6】 or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers thereof.

6. Formula (IIIc): 【Chemistry 7】 or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers thereof.

7. R 1 but, 【Chemistry 8】 The compound according to any one of claims 1 to 6, wherein

8. -L 1 -R 1 but, 【Chemistry 9】 The compound according to any one of claims 1 to 7, wherein

9. L 2 The compound of any one of claims 1 to 8, wherein is -C(=O)-.

10. L 2 Ga-(CH 2 ) n - and n is 0.

11. Z 1 and Z 2 is each independently CH.

12. Z 1 and Z 2 11. The compound of claim 1, wherein one of is N and the other is CH.

13. Z 1 is N and Z 2 13. The compound of claim 12, wherein is CH.

14. Z 2 is N and Z 1 13. The compound of claim 12, wherein is CH.

15. R 2 The compound of any one of claims 1 to 14, wherein is heteroaryl.

16. R 2 The compound of any one of claims 1 to 15, wherein is a 6-membered heteroaryl ring containing one or two N.

17. R 2 but, 【Chemistry 10】 each of which is selected from hydroxy, alkyl optionally substituted with alkoxy, haloalkyl, alkenyl or alkoxy optionally substituted with alkoxy, haloalkoxy, -N(R 4 ) 2 15. The compound of any one of claims 1 to 14, optionally substituted with one or two substituents independently selected from: and heteroaryl.

18. R 2 The compound of any one of claims 1 to 14, wherein is heterocycloalkyl or heterocycloalkenyl.

19. R 2 but, 【Chemistry 11】 each of which is selected from hydroxy, alkyl optionally substituted with alkoxy, haloalkyl, alkenyl or alkoxy optionally substituted with alkoxy, haloalkoxy, -N(R 4 ) 2 15. The compound of any one of claims 1 to 14, optionally substituted with one or two substituents independently selected from: and heteroaryl.

20. Z 3 The compound of any one of claims 1 to 19, wherein is CH.

21. X 3 But CH 2 21. The compound according to any one of claims 1 to 20, wherein

22. [Table 1] or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers thereof.

23. 11 C. 13 N, 15 O. 18 F, 52 Fe, 62 Cu, 64 Cu, 68 Ga, 74 As, 82 Rb, 89 Zr, 122 I and 124 23. The compound of any one of claims 1 to 22, labeled with one or more positron-emitting radionuclides selected from I.

24. 11 C. 13 N, 15 O and 18 24. The compound of claim 23, containing one or more positron-emitting radionuclides selected from F.

25. 25. An imaging agent comprising a compound according to claim 23 or 24, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers thereof.

26. An imaging agent comprising a compound according to any one of claims 1 to 24 or the imaging agent according to claim 25 for use in a method for producing a diagnostic image in an individual, the method comprising administering an effective amount of the imaging agent to the individual and producing an image of a body part or region of the individual.

27. 27. The imaging agent of claim 26, wherein generating an image of a body part or region of an individual comprises generating an image to detect the presence or absence of huntingtin protein (HTT protein) in the image and detecting the presence or absence of a pathological process.

28. 28. The imaging agent of claim 27, wherein the HTT protein is found in the basal ganglia.

29. 28. The imaging agent of claim 27, wherein the pathological process is a neurodegenerative disease.

30. 30. The imaging agent of claim 29, wherein the neurodegenerative disease is selected from Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, prion diseases, and spinocerebellar ataxias.

31. 30. The imaging agent of claim 29, wherein the neurodegenerative disease is Huntington's disease (HD).

32. 32. The imaging agent of any one of claims 26 to 31, wherein the effective amount of the imaging agent comprises 0.1 to 20 mCi.

33. 33. The imaging agent of claim 32, wherein the effective amount of the imaging agent comprises 10 mCi.

34. 34. The imaging agent of any one of claims 26 to 33, wherein generating an image comprises positron emission tomography (PET) imaging, PET with simultaneous computed tomography imaging (PET / CT), PET with simultaneous magnetic resonance imaging (PET / MRI), single photon emission computed tomography (SPECT) imaging, or a combination thereof.

35. 35. The imaging agent of claim 34, wherein generating an image comprises PET imaging.

36. 36. The imaging agent according to any one of claims 27 to 35, wherein the HTT protein is present as an aggregate thereof.

37. 37. The imaging agent according to any one of claims 27 to 36, wherein the HTT protein is a mutant.

38. 38. The imaging agent according to any one of claims 26 to 37, wherein the body part or body region is selected from the head, spinal cord, limbs, chest or abdomen.

39. 38. The imaging agent of any one of claims 26 to 37, wherein the body part or body region is the brain.

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