Deuterated compounds and imaging agents for imaging huntingtin protein - Patents.com

Abstract

Provided herein are certain compounds and imaging agents useful for detecting diseases or conditions associated with protein aggregation, compositions thereof, and methods of their use.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED PATENT APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 180,608, filed April 27, 2021, which is incorporated by reference herein for all purposes.

[0002] Provided herein are deuterated compounds and imaging agents, compositions thereof, and methods of their use that are useful for detecting, treating, or preventing diseases or conditions associated with protein aggregation. [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 non-invasive measurement of molecular and cellular mechanisms throughout the body in pre-clinical and clinical settings. Such measurements have widespread diagnostic utility and their use to assess treatment response and to aid in drug development is rapidly expanding.

[0004] Molecular probes labeled with positron-emitting radionuclides and associated PET imaging assays are being developed to target, detect, visualize, and quantify a variety of extracellular and intracellular molecules and processes associated with a variety of diseases, particularly neurodegenerative disorders whose pathology is in the brain. One such disease is Huntington's disease (HD). 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. HD is caused by an expanded CAG trinucleotide repeat in the exon-1 region of the huntingtin gene (HTT). The resulting polyglutamic acid domain expansion induces misfolding and conformational changes in mutant huntingtin (mHTT) protein, which can lead to the formation of protein aggregates. HD has a worldwide prevalence of 5-10 cases per 100,000 people, making it the most common inherited and monogenic neurodegenerative disorder.

[0005] As with other medical conditions, treatment of HD is ideally initiated at or before the first signs of disease. Early indicators of disease onset and reliable pharmacodynamic biomarkers of disease progression are therefore highly desirable. Imaging methods such as PET can provide such indicators.

[0006] PET involves the administration of a positron-emitting radionuclide tracer to a subject, followed by detection of the positron-emitting (annihilation) event in the body. Radionuclide tracers typically consist of a targeting molecule with one or more types of positron-emitting radionuclides incorporated within it. Summary of the Invention [Problem to be solved by the invention]

[0007] A useful radionuclide for incorporation into PET tracers is fluorine-18 due to its long half-life (109.8 min), availability of radiolabeling reagents, and ease of incorporation of fluorine atoms. However, some fluorides are susceptible to metabolic cleavage in biological systems, which leads to bone accumulation of fluorine-18 in the brain and prevents PET imaging of surrounding tissues. Thus, there is a need for compounds and imaging agents incorporating fluorine-18 that are sufficiently stable in vivo during the imaging process. [Means for solving the problem]

[0008] The present disclosure relates to compounds useful for imaging huntingtin protein. Some embodiments provide compounds described herein, e.g., compounds of formula I, formula Ia, formula Ib, formula X, or any other formula described herein, optionally labeled with one or more positron emitting isotopes. The present disclosure provides, in some cases, compounds useful for imaging huntingtin protein. 18 It is apparent that fluorine atoms, such as F, may be susceptible to environmental and / or metabolic cleavage in vivo. Thus, the compounds described herein are 18 Stabilizing functional groups are incorporated in the vicinity of F, which reduces or prevents such cleavage. In certain embodiments, the compounds include deuterated fluoroalkyl or deuterated fluoroalkoxy groups.

[0009] In some embodiments, an imaging agent is provided that comprises a compound of Formula I, Formula Ia, or Formula Ib, or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof. In some embodiments, the compound is 11 C. 13 N, 15 O, and 18 In certain embodiments, the positron-emitting isotopes are selected from F. 18 F. In some embodiments, the compounds contain deuterium in a position such that the fluorine atom is protected from environmental or metabolic cleavage in vivo.

[0010] 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, the compounds are 11 C. 13 N, 15 O, and 18 F. Such compositions are useful as tracers in PET imaging.

[0011] Also provided is a method of detecting the presence or absence of an aggregation-prone protein 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 region of the individual. The method may further comprise detecting changes in the distribution or amount of the protein, for example over time, in an individual subject.

[0012] In some embodiments, there is provided a compound or imaging agent for use in detecting the presence or absence of an aggregation-prone protein in an individual, the use comprising administering to the individual an effective amount of a compound or imaging agent as described herein and generating an image of a body part or region of the individual.

[0013] In some embodiments, a compound or imaging agent is provided for use as described herein, wherein generating an image of a body part or region of an individual comprises detecting the presence or absence of an aggregation-prone protein in the image. In some embodiments, a compound or imaging agent is provided for use as described herein, wherein the aggregation-prone protein is huntingtin protein (HTT protein). In some embodiments, a compound or imaging agent is provided for use as described herein, wherein HTT protein is found in the basal ganglia.

[0014] In some embodiments, there is provided a compound or imaging agent for the uses described herein, wherein the presence or absence of protein aggregates corresponds to the presence or absence of a neurodegenerative disease.

[0015] In some embodiments, there is provided a compound or imaging agent for use as described herein, wherein the neurodegenerative disease is selected from Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, prion disease, and spinocerebellar ataxia. In some embodiments, there is provided a compound or imaging agent for use as described herein, wherein the neurodegenerative disease is Huntington's disease (HD).

[0016] In some embodiments, there is provided a compound or imaging agent for a use as described herein, wherein an effective amount of the imaging agent comprises about 0.1 to about 20 mCi. In some embodiments, there is provided a compound or imaging agent for a use as described herein, wherein an effective amount of the imaging agent comprises about 10 mCi.

[0017] In some embodiments, there is provided a compound or imaging agent for use as described herein, 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. In some embodiments, there is provided a compound or imaging agent for use as described herein, wherein generating an image comprises PET imaging.

[0018] In some embodiments, there is provided a compound or imaging agent for the uses described herein, wherein the HTT protein is present as an oligomer or aggregate, or a combination thereof. In some embodiments, there is provided a compound or imaging agent for the uses described herein, wherein the HTT protein is a mutant.

[0019] In some embodiments, there is provided a compound or imaging agent for a use as described herein, wherein the body part or body region is the head, spinal cord, limbs, chest, or abdomen. In some embodiments, there is provided a compound or imaging agent for a use as described herein, wherein the body part or body region is the brain. [Brief description of the drawings]

[0020] [Figure 1] FIG. 1 illustrates a comparison of fluorine-18 compound 1-1 and compound 5-1 bone uptake following administration. [Diagram 2] FIG. 2 illustrates PET images for compound 1-1 and compound 5-1 at three different time periods after administration in mice. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] 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 disclosure, but rather is provided as a description of exemplary embodiments.

[0022] definition 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.

[0023] A compound described herein refers to a compound of any formula described herein including those of formula I, Ia, Ib, II, III, IV, V, VI, VII, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, or XIX, or an isotopically labeled analogue, pharma- ceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof, or a compound described anywhere herein including the Examples, or a compound of Table 1, or a labeled isomer of such a compound as defined herein, or an imaging agent or pharmaceutical composition comprising such a compound or labeled compound.

[0024] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent to the parent structure. For example, -C(O)NH 2 is attached to the parent structure through a carbon atom. Dashes preceding or at the end of chemical groups are for convenience; chemical groups may be illustrated with or without one or more dashes without losing their ordinary meaning. Wavy lines drawn through bonds in structures indicate specific points of attachment. Unless chemically or structurally required, no orientation or stereochemistry is indicated or implied by the order in which chemical groups are written or named.

[0025] Prefix “C” u~v" indicates that the following group has u to v carbon atoms, excluding further substitutions. For example, "C 1~6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms.

[0026] Reference herein to "about" a value or parameter includes (and describes) embodiments that are directed to the value or parameter per se. In certain embodiments, the term "about" includes ±10% of the stated amount. In other embodiments, the term "about" includes ±5% of the stated amount. In certain other embodiments, the term "about" includes ±1% of the stated amount. Additionally, the term "about X" includes the reference to "X." Additionally, the singular forms "a" and "the" include their plurals unless the context clearly dictates otherwise. Thus, for example, reference to "the compound" includes a plurality of such compounds, and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those of skill in the art.

[0027] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to an alkyl group having 1 to 20 carbon atoms (i.e., C 1~20 alkyl), 1 to 12 carbon atoms (i.e., C 1~12 alkyl), 1 to 9 carbon atoms (i.e., C 1~9 alkyl), 1 to 8 carbon atoms (i.e., C 1~8 alkyl), 1 to 6 carbon atoms (i.e., C 1~6 alkyl), or 1 to 4 carbon atoms (i.e., C 1~4 Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a particular number of carbons is named by a chemical name or specified by a molecular formula, all positional isomers having that number of carbons can be included; thus, for example, "butyl" refers to n-butyl (i.e., -(CH2 ) 3 CH 3 ), sec-butyl (i.e., -CH(CH 3 )CH 2 CH 3 ), isobutyl (i.e., -CH 2 CH(CH 3 ) 2 ) and tert-butyl (i.e., -C(CH 3 ) 3 ), and "propyl" includes n-propyl (i.e., -(CH 2 ) 2 CH 3 ) and isopropyl (i.e., -CH(CH 3 ) 2 ).

[0028] Alternative chemical names known to those skilled in the art may be used in place of the terms provided herein. For example, divalent groups, such as divalent "alkyl" groups, divalent "aryl" groups, etc., may also be referred to as "alkylene" or "arylene" groups, respectively. Also, unless expressly indicated otherwise (e.g., by a dash symbol), when a combination of groups is referred to herein as a moiety, e.g., arylalkyl or aralkyl, the last-mentioned group contains the atom that connects the moiety to the remainder of the molecule.

[0029] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkenyl), 2 to 8 carbon atoms (i.e., C 2~8 alkenyl), 2 to 6 carbon atoms (i.e., C 2~6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2~4Alkenyl refers to a hydrocarbon group having a saturated aryl group (such as aryl, ...

[0030] "Alkynyl" refers to an alkynyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkynyl), 2 to 8 carbon atoms (i.e., C 2~8 alkynyl), 2 to 6 carbon atoms (i.e., C 2~6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2~4 It refers to a hydrocarbon group having a saturated alkynyl group (alkynyl). The term "alkynyl" also includes such groups having triple and double bonds. Alkynyl groups also include "fluoroalkynyl", which refers to an alkynyl group that contains a carbon atom that is substituted with at least one fluorine atom. "Primary fluoroalkynyl" is a fluoroalkynyl that contains a saturated primary carbon atom that is substituted with a fluorine atom.

[0031] "Alkoxy" refers to the group "alkyl-O-". Example alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0032] "Alkylamino" refers to the group "alkyl-NH-". Examples of alkylamino groups include, for example, methylamino, ethylamino, iso-propylamino, tert-butylamino, and n-hexylamino. "Dialkylamino" refers to "(alkyl) 2"N-" group. Examples of dialkylamino groups include, for example, dimethylamino, diethylamino, (iso-propyl)(methyl)amino, (n-pentyl)(tert-butyl)amino, and di-n-hexylamino.

[0033] "Alkylthio" refers to the "alkyl-S-" group. "Alkylsulfinyl" refers to the "alkyl-S(O)-" group. "Alkylsulfonyl" refers to the "alkyl-S(O)-" group. 2 "Alkylsulfonylalkyl" refers to the -alkyl-S(O) group. 2 -refers to alkyl.

[0034] "Acyl" is -C(O)R y group (in the formula, R y refers to hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of acyls include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0035] "Amide" is -C(O)NR y R z "C-amide" groups, which refer to the -NR group y C(O)R z An "N-amide" group refers to the group, where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which is optionally substituted as defined herein, or R y and R z taken together form a cycloalkyl or heterocyclyl, each of which may be optionally substituted as defined herein.

[0036] "Amino" is -NRy R z group (in the formula, R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. In some embodiments, "amino" refers to NH 2 Refers to the base.

[0037] "Amidino" is -C(=NR y )NR z 2 group (in the formula, R y and R z refers independently to hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which is optionally substituted as defined herein.

[0038] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl refers to a ring system having 6 to 20 ring carbon atoms (i.e., C 6~20 aryl) or 6 to 10 carbon ring atoms (i.e., C 6~10 aryl). Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not in any way encompass or overlap with heteroaryl, as defined below. When one or more aryl groups are fused to a heteroaryl, the resulting ring system is a heteroaryl. When one or more aryl groups are fused to a heterocyclyl, the resulting ring system is a heterocyclyl.

[0039] "Arylalkyl" or "aralkyl" refers to the group "aryl-alkyl-".

[0040] "Carbamoyl" is -OC(O)NR yR z The "O-carbamoyl" group refers to the -NR group y C(O)OR z An "N-carbamoyl" group refers to the group (wherein R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which is optionally substituted as defined herein.

[0041] "Carboxyl ester" or "ester" refers to the -OC(O)R x and -C(O)OR x (In the formula, R x is alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0042] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having a single ring or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" refers to cycloalkenyl groups (i.e., cyclic groups having at least one double bond) and at least one sp 3 As used herein, cycloalkyl includes carbocyclic fused ring systems (i.e., at least one non-aromatic ring) having ring carbon atoms. 3~20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3~12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3~10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3~8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3~6cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Furthermore, the term cycloalkyl is intended to encompass any non-aromatic ring system, which may include fused aryl rings, regardless of the attachment to the rest of the molecule. Still further, cycloalkyl also includes "spirocycloalkyl", such as spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl. Cycloalkyl as a substituent may include spirocycloalkyl, if there are two positions on the carbon atom for substitution in the parent structure. Cycloalkyls may be optionally substituted at the carbon atom of the bond to the parent structure.

[0043] "Cycloalkoxy" refers to the group "-O-cycloalkyl."

[0044] "Cycloalkylalkyl" refers to the group "cycloalkyl-alkyl-".

[0045] "Guanidino" is -NR y C(=NR z )NR y R z (In the formula, each R y and R z refers independently to hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which is optionally substituted as defined herein.

[0046] "Imino" is -C(=NR y )R z group (in the formula, R y and R zeach independently refers to hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0047] "Imide" is -C(O)NR y C(O)R z group (in the formula, R y and R z each independently refers to hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0048] "Halogen" or "halo" refers to a substituent atom in Group VIIA of the periodic table, e.g., fluoro, chloro, bromo, or iodo.

[0049] "Haloalkyl" refers to an unbranched or branched alkyl group as defined above in which one or more (e.g., 1-6 or 1-3) hydrogen atoms, including up to and including all hydrogen atoms, have been replaced with a halogen. For example, if a residue is substituted with more than one halogen, it can also be referred to using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ("di") or three ("tri") halo groups, which may, but do not necessarily, be the same halogen. Perhaloalkyl groups are haloalkyl groups in which all hydrogen substituents have been replaced with halo. Examples of haloalkyl include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Haloalkyl groups also include "fluoroalkyl," which refers to an alkyl group substituted with at least one fluorine atom. A "primary fluoroalkyl" is a fluoroalkyl that includes a primary carbon atom that is substituted with a fluorine atom. A "deuterated haloalkyl" refers to a haloalkyl group that is substituted with at least one deuterium atom.

[0050] "Haloalkoxy" refers to an alkoxy group as defined above in which one or more (e.g., 1-6 or 1-3) hydrogen atoms, up to and including all hydrogen atoms, have been replaced with a halogen. Haloalkoxy groups also include "fluoroalkoxy," which refers to an alkoxy group substituted with at least one fluorine atom. "Primary fluoroalkoxy" is a fluoroalkoxy that includes a primary carbon atom substituted with a fluorine atom. "Deuterated haloalkoxy" refers to a haloalkoxy group substituted with at least one deuterium atom.

[0051] "Hydroxyalkyl" refers to an alkyl group, as defined above, in which one or more (eg, 1 to 6 or 1 to 3) hydrogen atoms are replaced with a hydroxy group.

[0052] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) of the alkyl chain are each independently replaced with the same or different heteroatom group, provided that the point of attachment to the remainder of the molecule is through a carbon atom. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. By way of example, one, two, or three carbon atoms may be independently replaced with the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR y -, -C(O)NR y -, -NR y C(O)-, -O-, -S-, -S(O)-, and -S(O) 2 -(In the formula, R y is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of heteroalkyl groups include, for example, ethers (e.g., -CH 2 OCH 3 , -CH(CH 3 )OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 etc.), thioethers (e.g., -CH 2 SCH 3 , -CH(CH 3 )SCH 3 , -CH 2 CH 2 SCH 3 , -CH 2 CH 2 SCH 2 CH 2 SCH 3 etc.), sulfones (e.g., -CH 2 S(O) 2 CH 3 , -CH(CH3 )S(O) 2 CH 3 , -CH 2 CH 2 S(O) 2 CH 3 , -CH 2 CH 2 S(O) 2 CH 2 CH 2 OCH 3 etc.), and aminoalkyl (e.g., -CH 2 NR y CH 3 , -CH(CH 3 )NR y CH 3 , -CH 2 CH 2 NR y CH 3 , -CH 2 CH 2 NR y CH 2 CH 2 NR y CH 3 etc., where R y is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. As used herein, heteroalkyl contains 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0053] "Heteroaryl" refers to an aryl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, and one or more (e.g., 1 to 3) N-oxides (-O - As used herein, heteroaryl refers to an aromatic group having 1 to 20 ring carbon atoms (i.e., C 1~20 Heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3~12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3~8 Heteroaryl) and 1-5 ring heteroatoms, 1-4 ring heteroatoms, 1-3 ring heteroatoms, 1-2 ring heteroatoms, or 1 ring heteroatom, each independently selected from nitrogen, oxygen, and sulfur. In certain instances, heteroaryl includes a 5-10 membered ring system, a 5-7 membered ring system, or a 5-6 membered ring system having 1-4 ring heteroatoms, 1-3 ring heteroatoms, 1-2 ring heteroatoms, or 1 ring heteroatom, each independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl ... Examples of such aryl groups include isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl and imidazo[1,5-a]pyridinyl, and the heteroaryl can be bonded through any ring of the fused system. Any aromatic ring system having a single or multiple fused rings containing at least one ring heteroatom, regardless of the bond to the rest of the molecule (i.e., through any one of the fused rings), is considered heteroaryl. Heteroaryl does not encompass or overlap with aryl as defined above.

[0054] "Heteroarylalkyl" refers to the group "heteroaryl-alkyl-".

[0055] "Heterocyclyl" refers to a saturated or partially unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, where the nitrogen or sulfur atom is optionally oxidized to an N-oxide, sulfinyl (-S(O)-), or sulfoxide (-S(O)-). 2 -). The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, spiro-heterocyclyl groups, and oxo-heterocyclyl groups. Heterocyclyls may be monocyclic or polycyclic, which polycyclic rings may be fused, bridged, or spiro. Regardless of the enumerated substituents, heterocyclyl may include one or more (e.g., 1-3) oxo (=O) or N-oxide (-O) groups, unless otherwise specified. - ) moiety. Heterocyclyl can be attached via a carbon atom or a heteroatom, where valence allows. Additionally, the term heterocyclyl encompasses any ring system, including non-aromatic rings or ring systems, containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring regardless of attachment to the remainder of the molecule. Heterocyclyl may have charged resonance structures that are aromatic (e.g., pyridin-2(1H)-one-1-yl). As used herein, heterocyclyl refers to a ring having 3-14 ring atoms, 3-10 ring atoms, 3-6 ring atoms, or 5-6 ring atoms, and / or 2-12 ring carbon atoms (i.e., C 2~12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C 2~10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C 2~8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C 3~12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C 3~8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C 3~6Heterocyclyl) and may have 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom. Examples of heterocyclyl groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, and the like. Heterocyclyl includes aryl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term "heterocyclyl" also includes "spiro-heterocyclyl." Examples of spiro-heterocyclyl rings include, for example, bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Heterocyclyl as a substituent may include spiro-heterocyclyl when there are two positions on the carbon atom for substitution in the parent structure. Examples of bridged heterocyclyl rings include, but are not limited to, 2,5-diazabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptanyl.Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be attached via either ring of the fused system. An "oxo-heterocyclyl" group is a heterocyclyl that includes at least one oxo substituent (e.g., 1, or 1-2 oxo substituents), regardless of whether additional substituents are allowed (i.e., an unsubstituted oxo-heterocyclyl includes oxo and no other substitutions). In some embodiments, the oxo-heterocyclyl includes a cyclic amide moiety.

[0056] "Heterocyclylalkyl" refers to the group "heterocyclyl-alkyl-".

[0057] "Oxime" is -CR y (=NOH) group (wherein R y refers to hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0058] "Sulfonyl" is -S(O) 2 R y group (in the formula, R y refers to hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0059] "Sulfinyl" is -S(O)R y group (in the formula, R yis hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.

[0060] "Sulfonamide" is -SO 2 NR y R z and -NR y SO 2 R z group (in the formula, R y and R z each independently refers to hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0061] The terms "optionally" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances in which said event or circumstance occurs and instances in which it does not occur. Also, the term "optionally substituted" refers to a group that is unsubstituted or substituted.

[0062] As used herein, the term "substituted" refers to any one or more (e.g., 1-5 or 1-3) hydrogen atoms being replaced with a non-hydrogen group, such as, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, arylalkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH 2 , =NNH 2, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O) 2 OH, sulfonamide, thiol, thioxo, N-oxide or -Si(R y ) 3 (In the formula, each R y refers to a group that is replaced by (which is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl).

[0063] In certain embodiments, "substituted" means that one or more (e.g., 1-5 or 1-3) hydrogen atoms are independently replaced with deuterium, halo, cyano, hydroxyl, imino, nitro, azido, oxo, thioxo, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, thioalkyl, haloalkoxy, cycloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -NR g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NR g S(=O) 1~2 R h , -C(=O)R g , -C(=O)OR g , -OC(=O)OR g , -OC(=O)R g , -C(=O)NR g R h , -OC(=O)NR g R h , -OR g , -SR g , -S(=O)R g , -S(=O) 2 R g , -OS(=O) 1~2 Rg , -S(=O) 1~2 OR g , -NR g S(=O) 1~2 NR g R h , =NSO 2 R g , =NOR g , -S(=O) 1~2 NR g R h ,-SCIENCE FICTION 5 , or -SCF 3 In certain embodiments, "substituted" also refers to a group in which one or more (e.g., 1-5 or 1-3) hydrogen atoms have been replaced with -C(=O)R. g , -C(=O)OR g , -C(=O)NR g R h , -CH 2 SO 2 R g , or -CH 2 SO 2 NR g R h In the above, R g and R h are the same or different and are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl; or R g and R h together with the atoms to which they are attached form a heterocyclyl ring optionally substituted with oxo, halo, or alkyl optionally substituted with oxo, halo, amino, hydroxyl, or alkoxy.

[0064] Polymers or similar indefinite structures arrived at by defining a substituent with infinitely more additional substituents (e.g., a substituted aryl with a substituted alkyl that is itself substituted with a substituted aryl group (which is further substituted with a substituted heteroalkyl group, etc.) are not intended to result from the above definition. Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl) substituted aryl) substituted aryl. Similarly, the above definition is not intended to encompass compounds with chemically infeasible or inseparable substitution patterns (e.g., a methyl substituted with five fluorines or a heteroaryl group with three consecutive oxygen ring atoms). Such unacceptable substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" may describe other chemical groups defined herein.

[0065] In certain embodiments, as used herein, the phrase "one or more" refers to 1 to 5. In certain embodiments, as used herein, the phrase "one or more" refers to 1 to 3.

[0066] Any compound or structure provided herein is intended to represent unlabeled forms of the compound as well as "isotopically enriched analogs." Isotopically enriched forms of the compound may also be referred to as "labeled." Isotopically enriched analogs have the structure depicted herein except that one or more atoms are enriched with an isotope having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 89, 90, 91, 92, 93, 94, 95, 9 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O.31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Isotopically enriched analogs generally include compounds having any isotopic enrichment above the natural abundance of the isotope (e.g., at the Earth's surface). Various isotopically labeled compounds, such as radioisotopes, e.g., 3 H, 18 F, 11 C, and 14 C and the like are included in the present disclosure. 18 F, 3 H, or 11 Compounds labeled with C may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radiation treatment of patients.

[0067] Also provided are "deuterated analogs" of the compounds described herein in which one or more hydrogens, e.g., hydrogens on a carbon atom, have been replaced with deuterium. Such compounds are synthesized, for example, by carrying out a reaction such as those provided herein or known in the art, and utilizing starting materials or reactants in which one or more hydrogen atoms have been replaced with deuterium atoms.

[0068] Isotopically labeled compounds of the present disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes described below or in the examples and preparations by substituting an available isotopically labeled reagent for a non-isotopically labeled reagent. Where a compound is described as a deuterated analog, the compound can be depicted with deuterium as a substituent.

[0069] The concentration of such heavier isotopes can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", it is understood that the position has hydrogen and its isotopes at their natural abundance.

[0070] In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0071] Also provided are isotopically enriched analogs, pharma- ceutically acceptable salts, prodrugs, tautomers, stereoisomers, and mixtures of stereoisomers of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials useful in the preparation of pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0072] The term "pharmaceutically acceptable salt" of a compound described herein refers to a salt that retains the biological effectiveness and properties of a given compound and is not biologically or otherwise unsuitable. A "pharmaceutically acceptable salt" or "physiologically acceptable salt" of a compound described herein includes, for example, an acid addition salt obtained by interacting a compound having a basic functional group with an acid, and a base addition salt obtained by interacting a compound having an acidic functional group with a base. If a compound is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the compound is a free base (e.g., an amine compound), an addition salt can be generated by dissolving the free base in a suitable organic solvent and treating the solution with an acid. Those skilled in the art will recognize various synthetic methods that may be used to prepare non-toxic, pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts of the compounds described herein can be prepared from inorganic and organic acids. Suitable inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Suitable organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, such as alkyl amines (i.e., NH 2 (alkyl)), dialkylamines (i.e., HN(alkyl) 2 ), trialkylamines (i.e., N(alkyl) 3 ), substituted alkylamines (i.e., NH 2 (substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl) 2), tri(substituted alkyl)amines (i.e., N(substituted alkyl) 3 ), alkenylamines (i.e., NH 2 (alkenyl)), dialkenylamines (i.e., HN(alkenyl) 2 ), trialkenylamines (i.e., N(alkenyl) 3 ), substituted alkenylamines (i.e., NH 2 (substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl) 2 ), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl) 3 , monocycloalkylamines, dicycloalkylamines or tricycloalkylamines (i.e., NH 2 (cycloalkyl), HN(cycloalkyl) 2 , N(cycloalkyl) 3 ), monoarylamines, diarylamines or triarylamines (i.e., NH 2 (aryl), HN(aryl) 2 , N(aryl) 3 ), cyclic amines (e.g., piperidine, piperazine, 1,4-diazabicyclo[2.2.2]octane), aromatic amines (e.g., pyridine, quinoline), or mixed amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0073] Some compounds described herein may exist as tautomers. For example, if a compound is depicted as containing an amide, the compound may exist as an imidic acid tautomer, and if a compound is depicted as containing a ketone, the compound may also exist as an enol tautomer. Regardless of which tautomer is depicted and regardless of the nature of the equilibrium between tautomers, the compound is understood by those skilled in the art to include both tautomers. Thus, for example, compounds containing amides are understood to include these imidic acid tautomers, and compounds containing imidic acids are understood to include these amide tautomers.

[0074] The compounds described herein may contain asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)-, or (D)- or (L)- with respect to amino acids. The compounds described herein are meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, for example (chiral) chromatography and / or fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography (HPLC). Where the compounds described herein contain double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both cis- and trans- or E- and Z-geometric isomers.

[0075] "Stereoisomer" refers to one of a set of compounds made up of the same atoms joined by the same bonds but with different three-dimensional structures. The various stereoisomers and mixtures thereof are intended to include "enantiomers," which refer to stereoisomeric compounds that are non-superimposable mirror images of one another.

[0076] A "diastereomer" is one of a series of stereoisomers that have at least two asymmetric atoms which are not mirror images of one another.

[0077] A "prodrug" is any molecule that releases a parent drug that is presumed to be active with the compounds described herein in vivo when such a prodrug is administered to a mammalian subject. A prodrug may be a form of a compound described herein that has been modified such that the modification 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 modification can be cleaved to the parent compound either in 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), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups, such as those 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," edited by H. Bundgaard, Elsevier, 1985; and Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is incorporated herein by reference in its entirety.

[0078] The methods described herein can be applied to cell populations in vivo or ex vivo. "In vivo" means within a living individual, such as within an animal or human. In this context, the methods described herein can be used therapeutically in an individual. "Ex vivo" means outside a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from an individual. Such samples can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used ex vivo to determine optimal schedules and / or dosing of administration of the disclosed compounds for a given indication, cell type, individual, and other parameters. Information gleaned from such uses can be used in the clinic for experimental purposes or to set up protocols for in vivo treatment. Other ex vivo uses to which the compounds and compositions described herein can be adapted are described below or will be apparent to one of skill in the art. Selected compounds can be further characterized to determine safety or tolerable doses in human or non-human subjects. Such properties can be determined using methods commonly known to those of skill in the art.

[0079] The above listed terms also include in vitro and ex vivo methods.

[0080] 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, through a designated point of attachment or bond.

[0081] The term "active agent" is used to refer to a compound that has biological activity in the treatment, amelioration, or prevention of a disease or condition. In some embodiments, an "active agent" is a compound having pharmaceutical utility or an isotopically labeled analog, pharma- ceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof. For example, an active agent may be an anti-neurodegenerative therapeutic agent.

[0082] The term "effective amount" refers to an amount of a compound, e.g., as described herein, sufficient to produce 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 effective to confer a therapeutic benefit, such as amelioration of symptoms, delay of disease progression, or prevention of disease, when administered to a human or non-human patient, e.g., a therapeutically effective amount may be an amount sufficient to reduce the symptoms of a disease as described herein. A (therapeutically) effective amount may vary depending on the subject and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the mode of administration, and can be readily determined by one of skill in the art.

[0083] 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.

[0084] The term "protein aggregates" as used herein refers to aggregates of proteins, which may be, for example, insoluble fibrillar amyloids comprising misfolded HTT protein molecules ("HTT protein aggregates") or misfolded β-amyloid protein molecules ("β-amyloid aggregates"). An "aggregation-prone protein" is a protein that is capable of forming such aggregates in its wild-type or mutant form.

[0085] 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 that includes the labeled compound. The positron-emitter labeled compound need only be enriched with a detectable isotope to a degree that allows detection using a technique appropriate for the particular application.

[0086] The term "PET imaging" (which may also be called positron emission tomography imaging), as used herein, refers to the production of images of internal structures of the human or animal body using positron emitter-labeled compounds.

[0087] The term “positron-emitting radionuclide” or “positron-emitting isotope” as used herein refers to a type of isotope in which protons inside the nucleus of a radionuclide emit positrons and electron neutrinos (ν e β refers to isotopes that exhibit a particular type of radioactive decay, called β decay, in which the isotope is converted into a neutron while emitting a positron. Some examples of positron-emitting isotopes include: 15 O. 13 N, 11 C. 18 F, 76 Br, and 124 Contains I.

[0088] The term "labeled," as used herein, refers to a compound that is associated with one or more positron-emitting isotopes that are greater than their natural abundance. For example, the labeled compounds described herein may contain one or more positron-emitting radionuclides in which atoms within the molecule (including atoms within the indicated substituents) are present as positron-emitting isotopes.

[0089] The term "tomography" as used herein refers to a segmental imaging technique. The images can be viewed individually as a series of two-dimensional slices, or together as a computer-generated three-dimensional display.

[0090] In some embodiments, the term "neurodegenerative disease" refers to a disease or condition in which the function of a subject's nervous system is impaired. Examples of neurodegenerative diseases include those described herein.

[0091] "Treatment" or "treating" means any treatment of a disease condition in a patient; a) inhibiting the disease (e.g., reducing one or more symptoms resulting from the disease or condition and / or lessening the severity of the disease or condition); b) delaying or halting the onset of clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or slowing the worsening or progression of the disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of the disease or condition); and / or c) palliating the disease, i.e., causing regression of clinical symptoms (e.g., causing remission of the disease state, providing partial or total relief of a disease or condition, enhancing the action of another drug, slowing the progression of a disease, improving quality of life and / or prolonging survival). Includes.

[0092] "Prevention" or "preventing" refers to any treatment of a disease or condition that keeps the clinical symptoms of the disease or condition from developing. The compounds, in some embodiments, can be administered to subjects (including humans) who are at risk (e.g., have genetic or epigenetic markers, have engaged in activities or have been exposed to environmental conditions associated with the disease or condition) or have a family history of the disease or condition.

[0093] "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 or patient is a mammal. In some embodiments, the subject or patient is a human.

[0094] The term "curie" (Ci) is a unit of measure of radioactivity and has its conventional meaning to those of ordinary skill in the art.

[0095] The term "diagnostic imaging," as used herein, refers to the production of pictures of internal structures of the human or animal body using electromagnetic radiation for diagnostic purposes.

[0096] The term "metabolically protected fluorine atom" refers to a compound containing a fluorine atom with adjacent functional groups that reduce cleavage to form difluorinated isomers. A metabolically protected fluorine atom may include one or more deuterium atoms adjacent to the fluorine atom (e.g., geminal or vicinal). Spatial (e.g., steric) blocking is also considered. A compound containing a metabolically protected fluorine atom may include a primary fluoroalkyl group or a primary fluoroalkoxy group that includes a protective functional group adjacent to the primary fluoride. Such compounds can be prepared by the methods described herein and known in the art.

[0097] It is to be understood that some features described herein that are described in the context of separate embodiments for clarity can also be provided in the form of a combination in a single embodiment. Conversely, various features described herein that are described in the context of a single embodiment for brevity can also be provided separately or in any suitable subcombination. All combinations of the embodiments with respect to the chemical groups represented by the variables contained in Formula I, Formula Ia, or Formula Ib, or any other formula, so long as such combinations result in stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity), are specifically included herein as if each and every combination were individually and explicitly recited. Furthermore, all subcombinations of the chemical groups recited in the embodiments describing such variables, as well as all subcombinations of the uses and medical applications described herein, are also specifically included herein as if each and every subcombination of the chemical groups and the subcombinations of the uses and medical applications were individually and explicitly recited herein. Additionally, some embodiments include every combination of one or more additional agents disclosed herein, as if each and every combination were individually and expressly listed.

[0098] [Table 1] TIFF2024516393000002.tif233153TIFF2024516393000003.tif225153

[0099] compound The present disclosure relates to compounds useful for imaging aggregation-prone proteins, such as huntingtin proteins. The compounds may contain metabolically protected fluorine atoms.

[0100] Some embodiments have formula Ia:

[0101] [ka] [In the formula, R 1 is C 1~6 Alkyl, C 2~6 Alkenyl, C 1~6 Haloalkyl, deuterated C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, deuterated C 1~6 Haloalkoxy, -O-alkylene-O-SO 2 -R 5 or -O-deuterated alkylene-O-SO 2 -R 5 and; R 5 is aryl optionally substituted with alkyl; R 2 does not exist or C 1~6 Alkyl, C 1~6 Haloalkyl, deuterated C 1~6 Haloalkyl, C 1~6 Haloalkoxy or deuterated C 1~6 haloalkoxy; R 3 Halo, C 1~6 Alkyl or C 1~6 is haloalkyl; n is 0, 1, or 2. or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0102] Some embodiments include compounds of formula Ib:

[0103] [ka] [In the formula, R 1 is C 1~6 Alkyl, C 2~6 Alkenyl, C 1~6 Haloalkyl, deuterated C 1~6 Haloalkyl, C 1~6 Alkoxy, deuterated C1~6 Haloalkoxy, -O-alkylene-O-SO 2 -R 5 or -O-deuterated alkylene-O-SO 2 -R 5 and; R 5 is aryl optionally substituted with alkyl; R 2 does not exist or C 1~6 Alkyl, C 1~6 Haloalkyl, deuterated C 1~6 Haloalkyl, C 1~6 Haloalkoxy or deuterated C 1~6 haloalkoxy; R 3 Halo, C 1~6 Alkyl or C 1~6 is haloalkyl; n is 0, 1, or 2. or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0104] Some embodiments include compounds of formula I:

[0105] [ka] [In the formula, R 1 is C 1~6 Alkyl, C 2~6 Alkenyl, C 1~6 Haloalkyl, deuterated C 1~6 Haloalkyl, C 1~6 Alkoxy, deuterated C 1~6 Haloalkoxy, or -O-alkylene-O-SO 2 -R 5 and; R 5 is aryl optionally substituted with alkyl; R 2 does not exist or C 1~6 Alkyl, C 1~6 Haloalkyl, deuterated C1~6 Haloalkyl, C 1~6 Haloalkoxy or deuterated C 1~6 haloalkoxy; R 3 Halo, C 1~6 Alkyl or C 1~6 is haloalkyl; n is 0, 1, or 2. or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0106] In some embodiments, the compound of Formula I, Formula Ia, or Formula Ib has Formula II:

[0107] [ka] or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0108] In some embodiments, the compound of Formula I, Formula Ia, or Formula Ib has Formula III:

[0109] [ka] or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0110] In some embodiments, the compound of Formula I, Formula Ia, or Formula Ib has Formula IV:

[0111] [ka] [In the formula, m is 0, 1, or 2; 11 and each R 12 are independently selected from hydrogen and deuterium, and at least one R 11 or R 12is deuterium] or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0112] In some embodiments, the compound of Formula I, Formula Ia, or Formula Ib has Formula V:

[0113] [ka] [In the formula, m is 0, 1, or 2; 11 and each R 12 are independently selected from hydrogen and deuterium, and at least one R 11 or R 12 is deuterium] or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0114] In some embodiments, the compound of Formula I, Formula Ia, or Formula Ib has Formula VI:

[0115] [ka] [In the formula, m is 0, 1, or 2; 11 and each R 12 are independently selected from hydrogen and deuterium, and at least one R 11 or R 12 is deuterium] or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0116] In some embodiments, the compound of Formula I, Formula Ia, or Formula Ib has Formula VII:

[0117] [ka] [In the formula, m is 0, 1, or 2; 11 and each R 12 are independently selected from hydrogen and deuterium, and at least one R 11 or R 12 is deuterium] or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0118] In some embodiments, the compound comprises a metabolically protected fluorine atom. The compound having a metabolically protected fluorine atom may comprise a primary fluorine having 1-4 geminal and / or vicinal deuterium atoms. The compound having a metabolically protected fluorine atom may comprise a deuterated C 1~6 Haloalkyl or deuterated C 1~6 The metabolically protected fluorine atom may be a deuterated fluorine-containing group selected from fluoroalkyl, fluoroalkenyl, and fluoroalkynyl groups. The compound has the structure

[0119] [ka] [In the formula, m is 0, 1, or 2; 11 and each R 12 are independently hydrogen, deuterium, and C 1~3 alkyl, and at least one R 11 or R 12 is deuterium and the wavy line indicates the point of attachment to the parent structure], for example, a substituent having a structure having any formula provided herein. 11 and each R 12 is deuterium.

[0120] In some embodiments, the compound having a metabolically protected fluorine has the structure

[0121] [ka] where the wavy line indicates the point of attachment to the parent structure. The bond at the wavy line may be attached through a linking functional group, for example, through an oxygen atom to form an ether.

[0122] In some embodiments, the compound contains at least one fluoro. In some embodiments, the compound contains one fluoro. In some embodiments, R 1 contains a fluorine atom.

[0123] In some embodiments, R 1 or R 2 One of them is deuterated C 1~6 Haloalkyl, deuterated C 1~6 Haloalkoxy, or moiety

[0124] [ka] [In the formula, m is 0, 1, or 2; 11 and each R 12 are independently hydrogen, deuterium, and C 1~3 alkyl, and at least one R 11 or R 12 is deuterium and the wavy line indicates the point of attachment to the parent structure. Includes.

[0125] In some embodiments, R 1 or R 2 One of them is

[0126] [ka] [In the formula, m is 0, 1, or 2; 11 and each R 12 are independently hydrogen, deuterium, and C 1~3 alkyl, and at least one R 11 or R 12 is deuterium] It is.

[0127] In some embodiments, each R 11 and each R 12 is deuterium.

[0128] In some embodiments, R 1 is deuterated C 1~6 Haloalkyl or deuterated C 1~6 It is haloalkoxy.

[0129] In some embodiments, R 1 is deuterated C 1~6 In some embodiments, R 1 is C 1~6 It is a fluoroalkoxy.

[0130] In some embodiments, R 1 -O-CD 2 -CD 2 -F.

[0131] In some embodiments, each R 11 and each R 12 are independently selected from halo, hydrogen, and deuterium, and at least one R 11 or R 12 is deuterium or halo. In some embodiments, at least one R 11 and at least one R 12 is halo. In some embodiments, each R 11 and each R 12 is fluoro.

[0132] In some embodiments, R 2 is C 1~6 Alkyl or C 1~6 It is haloalkoxy.

[0133] In some embodiments, R 2 is C 1~6 It is an alkyl.

[0134] In some embodiments, n is 0.

[0135] In some embodiments, R 3 is fluoro.

[0136] In some embodiments, a compound of Formula I, Formula Ia, or Formula Ib is labeled with one or more positron emitting isotopes.

[0137] In some embodiments, the compound is 11 C. 13 N, 15 O, and 18 It contains one or more positron emitting isotopes selected from F.

[0138] In some embodiments, an imaging agent is provided that comprises a compound of Formula I, Formula Ia, or Formula Ib, or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0139] Also provided are additional compounds described herein. In some embodiments, a compound selected from Table 1, or an isotopically labeled analog, pharma- ceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof is provided.

[0140] In some embodiments, a compound selected from the compounds of Table 1 is provided, optionally labeled with one or more positron emitting isotopes, or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0141] In some embodiments, a pharmaceutical composition is provided that includes a compound described herein, or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, and a pharma- ceutically acceptable excipient.

[0142] Non-metallic positron-emitting isotopes can be covalently bound to the compounds described herein by reactions known from the state of the art. It is understood that if the positron-emitting isotope is a metallic positron emitter, labeling may require the use of a chelating agent. Such chelating agents are known from the state of the art.

[0143] In some embodiments, a compound is provided that is selected from the compounds described in the Examples section provided herein.

[0144] Also provided is a compound selected from Table 1, or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof:

[0145] [Table 2] TIFF2024516393000018.tif175144

[0146] In some embodiments, the compound has formula X:

[0147] [ka] [In the formula, Ring A is a 9-membered bicyclic heteroaryl; Ring B is a 6-membered heterocyclyl, a 6-membered oxo-heterocyclyl, or a 6-membered heteroaryl; Ring C is a 6-membered heteroaryl; Z is O, S, NH, or N(C 1~3 alkyl); L is CH 2 , CH(C 1~3 alkyl), C(C 1~3 Alkyl) 2 or C(O); R 1 are cyano, halo, hydroxy, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C2~6 Alkynyl, C 1~6 Haloalkyl, deuterated C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, deuterated C 1~6 Haloalkoxy, C 1~6 Alkylthio, C 3~8 Cycloalkyl, heterocyclyl, heteroaryl, amino, alkylamino, dialkylamino, or -O-alkylene-O-SO 2 -R 5 and; R 5 is aryl optionally substituted with alkyl; R 2 is absent or is cyano, halo, hydroxy, nitro, C 1~6 Alkyl, C 1~6 Haloalkyl, deuterated C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, deuterated C 1~6 Haloalkoxy, C 1~6 Alkylthio, C 3~8 cycloalkyl, heterocyclyl, heteroaryl, amino, alkylamino, or dialkylamino; R 3 are cyano, halo, hydroxy, nitro, C 1~6 Alkyl, C 1~6 Haloalkyl, deuterated C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, deuterated C 1~6 Haloalkoxy, C 1~6 Alkylthio, C 3~8 cycloalkyl, heterocyclyl, heteroaryl, amino, alkylamino, or dialkylamino; R 4 are cyano, halo, hydroxy, nitro, C 1~6 Alkyl, C 1~6 Haloalkyl, deuterated C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6Haloalkoxy, deuterated C 1~6 Haloalkoxy, C 1~6 Alkylthio, C 3~8 cycloalkyl, heterocyclyl, heteroaryl, amino, alkylamino, or dialkylamino; n1 is 0, 1, or 2; n2 is 0, 1, or 2; R 1 , R 2 , R 3 , or R 4 One of them is deuterated C 1~6 Haloalkyl, deuterated C 1~6 Haloalkoxy, or moiety

[0148] [ka] (In the formula, m is 0, 1, or 2, and each R 11 and each R 12 are independently hydrogen, deuterium, and C 1~3 alkyl, and at least one R 11 or R 12 is deuterium and the wavy line indicates the point of attachment to the parent structure) [Including or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0149] In some embodiments, the compound has formula XI:

[0150] [ka] [In the formula, X is NR 4 , O, and S; Y is CR 4 and N; Z 1 , Z 2 , Z 3 , and Z 4 is independently selected from CH and N, with the proviso that Z1 , Z 2 , Z 3 , and Z 4 at least two of are CH; R 1 is selected from heteroaryl, heterocycloalkenyl, and heterocycloalkyl, each of which is optionally substituted with one or two groups independently selected from cyano, halo, lower alkyl optionally substituted with amino, alkylamino, or di(alkyl)amino, lower alkoxy optionally substituted with lower alkoxy, optionally substituted amino, haloalkyl, di(alkyl)aminocarbonyl, alkylaminocarbonyl, and aminocarbonyl; R 1 is phenyl optionally substituted with 1 or 2 groups independently selected from cyano, heteroaryl, halo, phenoxy, benzyloxy, heteroaryl, lower alkyl, lower alkyl optionally substituted with amino, (alkyl)amino, or di(alkyl)amino, lower alkoxy, optionally substituted amino, di(alkyl)aminocarbonyl, alkylaminocarbonyl, and aminocarbonyl; L 1 is -O-, and L 2 is -(CR 7 R 8 ) m -or- 7 R 8 ) m -O-; or L 1 -NR 3 - and L 2 is -C(O)- or -(CR 7 R 8 ) m -or- L 1 -NR 3 - and L 2 is -C(O)(O)(CR 7 R 8 ) m -or- L1 -NR 3 - and L 2 is -C(O)(CR 7 R 8 ) m (O)-; or L 1 -NR 3 - and L 2 is -C(O)(CR 7 R 8 ) m -or- L 1 -NR 3 - and L 2 is -C(O)CR 7 =CR 8 -or- L 1 is -C(O)-, and L 2 -NR 3 -or- L 1 is -(CR 7 R 8 ) m - and L 2 -NR 3 -, -C(O)-, or -O-; or L 1 does not exist, L 2 does not exist; or L 1 , L 2 together is -CH=CH-, -C≡C-, or heterocyclylene; L 3 is -CH=CH- or L 3 does not exist; R 2 is selected from heterocycloalkyl, aryl, and heteroaryl, each of which is -OC(O)-R 6 , -C(O)OR 6 , amino, Hello, Haloalkyl, Phenyl, Heteroaryl, Cyano, (lower alkyl)thio, Phenoxy, Phenoxymethyl, Heteroaryloxy, heteroaryloxy substituted with lower alkyl; Hydroxyl, lower alkenyloxy, Lower alkoxy, lower alkoxy, amino, (alkyl)amino, (dialkyl)amino, heterocycloalkyl, heteroaryl, or lower alkoxy substituted with halo; Lower alkyl, and Amino, (alkyl)amino, (dialkyl)amino, lower alkyl substituted with hydroxyl or lower alkoxy and optionally substituted with 1 or 2 groups selected from: R 3 is selected from hydrogen and lower alkyl; R 4 is selected from hydrogen, halo, cyano, and lower alkyl; R 5 is selected from lower alkyl, lower alkoxy, and halo; R 6 is lower alkyl; R 7 is selected from hydrogen, hydroxyl, trifluoromethyl, and lower alkyl; R 8 is selected from hydrogen and lower alkyl; n is 0 or 1; m is 0, 1, or 2. or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, The compound of formula XI, or a pharma- ceutically acceptable salt thereof, is labeled with one or more positron emitting isotopes; The compounds contain metabolically protected fluorine atoms.

[0151] In some embodiments, the compound has formula XII:

[0152] [ka] [In the formula, X is (CR 3 =CR 3 ), O, NH, and S; Y is CR 3 and N; For each occurrence, R 3 is independently selected from hydrogen, halo, cyano, and lower alkyl; Z 1 , Z 2 , Z 3 , and Z 4 is independently selected from CH and N, with the proviso that Z 1 , Z 2 , Z 3 , and Z 4 at least two of are CH; R 1 is selected from aryl, heteroaryl, and heterocycloalkyl, each of which is optionally substituted with 1 or 2 groups independently selected from alkynyl, cyano, optionally substituted amino, halo, and lower alkyl optionally substituted with optionally substituted amino; L 1 is C(O)O, O, and NR 4 or L 1 does not exist; R 4 is selected from hydrogen and lower alkyl; L 2 is (CH 2 ) m where m is 0, 1, or 2; R 2 is selected from hydrogen, hydroxyl, lower alkyl, lower haloalkyl, halo, and lower alkoxy; R 5 is selected from lower alkyl, lower alkoxy, and halo; n is 0 or 1; or R 2 and R 5 may be joined together with any intervening atoms to form a 5- to 7-membered heterocycloalkyl ring. or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, The compound of formula XII, or a pharma- ceutically acceptable salt thereof, is labeled with one or more positron emitting isotopes; The compounds contain metabolically protected fluorine atoms.

[0153] In some embodiments, the compound has formula XIII:

[0154] [ka] [In the formula, Z 1 , Z 2 , Z 3 , and Z 4 is independently selected from CH and N, with the proviso that Z 1 , Z 2 , Z 3 , and Z 4 at least two of are CH; R 1 is selected from aryl, heteroaryl, and heterocycloalkenyl, each of which is optionally substituted with 1 or 2 groups independently selected from alkynyl, heteroaryl, cyano, optionally substituted amino, halo, lower alkyl, and lower alkyl substituted with optionally substituted amino; L 1 is O and NR 4 Selected from; R 4 is selected from hydrogen and lower alkyl; L 2 is (CH 2 ) m where m is 0, 1, or 2; R 2is selected from hydrogen, aryl, aryl substituted with hydroxyl or lower alkoxy, heteroaryl, and heteroaryl substituted with hydroxyl or lower alkoxy; R 5 is selected from lower alkyl, lower alkoxy, halo, and oxo (as substituents on a heterocycloalkyl ring); n is 0 or 1. or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, The compound of formula XIII, or a pharma- ceutically acceptable salt thereof, is labeled with one or more positron emitting isotopes; The compounds contain metabolically protected fluorine atoms.

[0155] In some embodiments, the compound has formula XIV:

[0156] [ka] [In the formula, m is 0, 1, or 2; n is 1 or 2; J is C(=O) or -CH 2 - and; X is S or N; Y is CH or N; Z is CH or N; W is N or S; For each occurrence, R 1 is independently selected from halo, lower alkoxy, hydroxy, aryl, heteroaryl, cycloalkoxy, or lower alkyl, and lower alkoxy, cycloalkoxy, lower alkyl, aryl, or heteroaryl is lower alkoxy, alkenyl, -NR 4 R 5 each optionally substituted with 1, 2, or 3 groups independently selected from heteroaryl optionally substituted with 1 to 3 lower alkoxy, halo, or heteroaryl; R2 is hydrogen or lower alkyl; R 3 is alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, or heteroaralkyl, each of which is selected from the group consisting of hydroxy, lower alkoxy or lower alkoxy optionally substituted with halo, lower alkyl optionally substituted with halo, halo, heteroaryl, -(CH 2 ) t NR 4 R 5 , oxo, cyano, or -C(O)-NR 4 R 5 or R 2 and R 3 taken together with the nitrogen to which they are attached, represent hydroxy, lower alkoxy, lower alkyl, halo, or -C(O)-NR 4 R 5 forming a heterocycloalkyl ring, optionally substituted with 1, 2, or 3 groups independently selected from: t is 0, 1, or 2; Each R 4 is independently selected from hydrogen or lower alkyl; Each R 5 is independently selected from hydrogen or lower alkyl; or R 4 and R 5 taken together with the nitrogen to which they are attached, represent hydroxy, lower alkoxy, lower alkyl, halo, or -C(O)-NR 6 R 7 forming a heterocycloalkyl ring, optionally substituted with 1, 2, or 3 groups independently selected from: Each R 6 is independently selected from hydrogen or lower alkyl; Each R 7 are independently selected from hydrogen or lower alkyl. or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, The compound of formula XIV, or a pharma- ceutically acceptable salt thereof, is labeled with one or more positron emitting isotopes; The compounds contain metabolically protected fluorine atoms.

[0157] In some embodiments, the compound has formula XV:

[0158] [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 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 1is aryl or heteroaryl, each of which is selected from halogen, haloalkyl, hydroxy, alkyl, alkoxy, haloalkoxy, and -N(R 4 ) 2 and 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 and optionally substituted with 1 or 2 substituents independently selected from: p is 0, 1, or 2; Each R 3 is independently 1~4 Alkyl or two R on the same carbon 3 forms an oxo, R 3 teeth,

[0159] [ka] one or more ring carbon atoms may be substituted; Each R 4 are independently H or C 1~4 is alkyl] or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, The compound of formula XV, or a pharma- ceutically acceptable salt thereof, is labeled with one or more positron emitting isotopes; The compounds contain metabolically protected fluorine atoms.

[0160] In some embodiments, the compound has formula XVI:

[0161] [ka] [In the formula, A 1 is C; A 2 is C or N; A 3 CR 21 , N.R. 3 or N; A 4 CR 22 , N.R. 3 or N; A 5 CR 23 , N.R. 3 or N; -A 1 -A 2 -A 3 -A 4 -A 5 - the ring Z formed by is a 5-membered heteroaryl having up to 3 nitrogen atoms; R 21 , R 22 , and R 23 each independently represents hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy or C 3~6 is cycloalkyl; Each R 3 are independently hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, or C 3~6 is cycloalkyl; A 6 CR 11 Or N and A 7 CR 12 Or N and A 8 CR 13 Or N and A 9 CR 14 Or N and A 6 , A 7 , A 8 , and A 9 no more than two of are N; R 11 , R 12 , R 13 , and R 14 Each of the groups is selected from hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy or C 1~4 haloalkoxy; X 1 is C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 aryl, heteroaryl, or heterocyclyl; X 1 is 1 to 4 R 4 is optionally replaced by; Each R 4 are independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy or C 1~4 haloalkoxy; X 2 is O, S, or NR 5 ;R 5 is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 is alkoxy; L is -(C(R 6 ) 2 ) m -wherein m is 1, 2, 3, or 4; Each R 6 are independently hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy or C 1~4 haloalkoxy; or two R 6 forms a 3- to 6-membered ring together with any intervening atoms; L 1 are C(O), C(O)NR a, N.R. a C(O), or O, or L 1 does not exist; R a is hydrogen, C 1~6 Alkyl or C 1~6 is haloalkyl; L 2 is 1 to 4 R 7 C, optionally replaced by 1~2 alkylene or L 2 does not exist; Each R 7 are independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy or C 1~4 haloalkoxy] or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, The compound is labeled with one or more positron-emitting isotopes; The compounds contain metabolically protected fluorine atoms.

[0162] In some embodiments, the compound has formula XVII:

[0163] [ka] [In the formula, R 1 is hydrogen, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 haloalkoxy, or phenyl; R 2 is hydrogen, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy or C 1~6 haloalkoxy; R 3 is hydrogen, C1~6 Alkyl or C 1~6 is haloalkyl; X 1 is C 6~10 aryl or heteroaryl, each of which is selected from 1 to 4 R 4 is optionally replaced by; X 2 is heteroaryl, heterocyclyl, or oxo-heterocyclyl, each of which is selected from 1 to 4 R 6 is optionally replaced by; Each R 4 are independently halo, cyano, hydroxy, nitro, amino, alkylamino, dialkylamino, R 5 C, optionally replaced by 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, R 5 C, optionally replaced by 1~6 Alkoxy or C 1~6 haloalkoxy; Each R 5 are independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, or C 1~6 is alkoxy; Each R 6 are independently halo, cyano, hydroxy, nitro, amino, alkylamino, dialkylamino, R 7 C, optionally replaced by 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, R 7 C, optionally replaced by 1~6 Alkoxy or C 1~6 haloalkoxy; Each R 7 are independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, or C 1~6 is alkoxy; L is (C(R 8 ) 2 ) n and; n is 0, 1, or 2; Each R 8 are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 Is it alkoxy; or R 3 or R 8 One of the groups, together with the intervening atom, is R 6 forming a 3- to 6-membered saturated or partially unsaturated ring having the formula or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, The compound is labeled with one or more positron-emitting isotopes; The compounds contain metabolically protected fluorine atoms.

[0164] In some embodiments, the compound has Formula XVIII:

[0165] [ka] [In the formula,

[0166] [ka] teeth,

[0167] [ka] or

[0168] [ka] and; R 1 is hydrogen, if present, C 1~6 Alkyl or C 1~6 is haloalkyl; R 10 is hydrogen, if present, C 1~6 Alkyl or C 1~6 is haloalkyl; Ring A is a 5-6 membered heteroaryl; X is CR 11 or N; R 11 is hydrogen, cyano, hydroxy, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, or C 1~6 is alkoxy; Y 1 CR 12 or N; Y 2 CR 13 or N; R 12 and R 13 Each of these is hydrogen, hydroxy, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, or C 1~6 is alkoxy; R 2 is hydrogen, hydroxy, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, or C 1~6 is alkoxy; L is C optionally substituted with 1 to 6 fluoro. 1 ~C 3 is alkylene; R 3 is hydrogen, fluoro, C 1~6 Alkyl or C 1~6 is haloalkyl; Each R 4 are independently cyano, hydroxy, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, or C 1~6 is alkoxy; Each R 5 are independently cyano, hydroxy, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, or C 1~6 is alkoxy; R 6 is hydrogen, cyano, hydroxy, halo, C 1~6 Alkyl, -SO 2 F or L 1 -R7 and; L 1 -O-, -SO 2 - or -OSO 2 - and; R 7 is hydrogen, C 1~6 Alkyl or C 1~6 haloalkyl, R 7 C 1~6 Alkyl or C 1~6 Haloalkyl is -SO 2 -aryl, -OSO 2 -aryl, optionally substituted with 1 to 6 deuterium atoms, or combinations thereof; 2 -aryl or -OSO 2 -Aryl is cyano, hydroxy, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, or C 1~6 is further optionally substituted with alkoxy; m is 0, 1, 2, or 3; n is 0, 1, or 2. or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, The compound of formula XVIII, or a pharma- ceutically acceptable salt thereof, is labeled with one or more positron emitting isotopes; The compounds contain metabolically protected fluorine atoms.

[0169] In some embodiments, the compound has Formula XVIII:

[0170] [ka] [In the formula,

[0171] [ka] teeth,

[0172] [ka] or

[0173] [ka] and; R 1 is hydrogen, if present, C 1~6 Alkyl or C 1~6 is haloalkyl; R 10 is hydrogen, if present, C 1~6 Alkyl or C 1~6 is haloalkyl; Ring A is a 5-6 membered heteroaryl; X is CR 11 or N; R 11 is hydrogen, cyano, hydroxy, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, or C 1~6 is alkoxy; Y 1 CR 12 or N; Y 2 CR 13 or N; R 12 and R 13 Each of these is hydrogen, hydroxy, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, or C 1~6 is alkoxy; R 2 is hydrogen, hydroxy, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, or C 1~6 is alkoxy; L is C optionally substituted with 1 to 6 fluoro. 1 ~C 3 is alkylene; R 3 is hydrogen, fluoro, C 1~6 Alkyl or C 1~6 is haloalkyl; Each R 4are independently cyano, hydroxy, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, or C 1~6 is alkoxy; Each R 5 are independently cyano, hydroxy, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, or C 1~6 is alkoxy; R 6 is hydrogen, cyano, hydroxy, halo, C 1~6 Alkyl, -SO 2 F or L 1 -R 7 and; L 1 -O-, -SO 2 - or -OSO 2 - and; R 7 is hydrogen, C 1~6 Alkyl or C 1~6 haloalkyl, R 7 C 1~6 Alkyl or C 1~6 Haloalkyl is -SO 2 -aryl, -OSO 2 -aryl, optionally substituted with 1 to 6 deuterium atoms, or combinations thereof; 2 -aryl or -OSO 2 -Aryl is cyano, hydroxy, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, or C 1~6 is further optionally substituted with alkoxy; m is 0, 1, 2, or 3; n is 0, 1, or 2. or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, The compounds contain metabolically protected fluorine atoms.

[0174] In some embodiments, the compound has formula XIX:

[0175] [ka] [In the formula, L 1 is -CH=CH- or L 1 does not exist; R 1 is selected from phenyl or heteroaryl, each of which is Cyano, Hello, Heteroaryl, Lower alkyl, lower alkyl substituted with 1 or 2 substituents independently selected from lower alkoxy substituted with heteroaryl; -C(O)O-lower alkyl, Hydroxyl, lower alkynyloxy, lower alkoxy, and below, Hello, Heterocycloalkyl, Heteroaryl, heteroaryl substituted with lower alkoxy; optionally substituted amino; Heteroaryl-substituted alkyl, and Alkyl substituted with heteroaryl substituted with lower alkoxy Lower alkoxy substituted with 1 or 2 substituents independently selected from or R 1 is phenyl substituted with two groups which, together with the carbon atom to which they are attached, form a heterocycloalkenyl ring, said phenyl being Hello, Heteroaryl, and Optionally substituted amino and optionally further substituted with a substituent selected from: L 2 is -N(R 4)- or L 2 does not exist; R 2 teeth 、 hydrogen, Lower alkyl, and lower alkoxy, amino, (alkyl)amino, (dialkyl)amino, or lower alkyl substituted with hydroxy Selected from; For each occurrence, R 3 is, independently, Hello, Cyano, Lower alkoxy, lower alkyl optionally substituted with amino, (alkyl)amino, or di(alkyl)amino, and Ethynyl optionally substituted with tri(alkyl)silyl Selected from; R 4 is selected from hydrogen and lower alkyl; m is 0, 1, or 2. or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, The compound of formula XIX, or a pharma- ceutically acceptable salt thereof, is labeled with one or more positron emitting isotopes; The compounds contain metabolically protected fluorine atoms.

[0176] Diagnostic Methods and Uses In some embodiments, a method of detecting the presence or absence of an aggregation-prone protein in an individual is provided, comprising administering to the individual an effective amount of a compound or imaging agent described herein, and generating an image of a body part or region of the individual. Generating an image of a body part or region of the individual may include generating an image and detecting the presence or absence of the aggregation-prone protein in the image. Thus, the compounds disclosed herein are useful for detecting diseases or conditions mediated at least in part by proteins prone to protein aggregation. In some embodiments, the presence or absence of protein aggregates corresponds to the presence or absence of a neurodegenerative disease. In some embodiments, the neurodegenerative disease is selected from Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, prion disease, and spinocerebellar ataxia.

[0177] Methods are provided for producing diagnostic images using positron emission tomography (PET) and for detecting the presence or absence of proteins prone to aggregation. PET imaging may be performed as known to those skilled in the art or as follows. PET imaging may involve administration of a positron-emitting radionuclide tracer, such as a compound or imaging agent described herein, to an individual. The tracer is then allowed to bind to the protein of interest for a sufficient period of time, at which point the individual is placed in a scanning device equipped with a scintillation detector ring. The emitted positron travels a short (isotope-dependent) distance within the tissues of the individual 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. Photons that do not result in a pair are ignored.

[0178] 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, and methods of detecting the presence or absence of aggregation-prone proteins are also provided. Generally, computed tomography uses x-rays or gamma rays to detect brain structures, while magnetic resonance imaging uses magnetic fields and radio waves.

[0179] Thus, the compounds or imaging agents described herein can be administered by methods known in the art, including those described herein. The compounds or imaging agents can enter the circulation and bind to proteins prone to aggregation, or aggregates thereof. If the compounds or imaging agents are labeled with a positron-emitting isotope, the emitted particles can be detected.

[0180] In some embodiments, the compound or imaging agent is administered to the vascular system of the individual. 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 brain of the individual, for example, a portion into which the compound is distributed.

[0181] Also provided are methods of generating diagnostic images in biological samples, and methods of detecting the presence or absence of aggregation-prone proteins, 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.

[0182] Also provided is a method 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, comprising administering an effective amount of a compound or imaging agent described herein; generating an image and detecting the presence or absence of huntingtin protein (HTT protein) in the image; and detecting the presence or absence of a pathological process, such as a neurodegenerative disease. In some embodiments, the HTT protein is present as a monomer, oligomer, or aggregate, or a combination thereof. In some embodiments, the protein prone to aggregation is huntingtin protein (HTT protein). The HTT protein may be a mutant. In some embodiments, the HTT protein is found in the brain, for example, in the basal ganglia.

[0183] In some embodiments, the body part or region is selected from the head, spinal cord, limbs, chest, and / or abdomen. In some embodiments, the body part or region is the brain. In some embodiments, the HTT protein is found in the basal ganglia. In some embodiments, the aggregation-prone protein, e.g., 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 aggregation-prone protein, e.g., HTT protein, is present in the basal ganglia, cortex, hippocampus, and / or brainstem of the brain of the individual. In some embodiments, the aggregation-prone protein, e.g., HTT protein, is present as a monomer, oligomer, or aggregate, or a combination thereof.

[0184] In some embodiments, the individual has or is found to have Huntington's disease.

[0185] Also provided are methods of detecting the presence or absence of a pathological process associated with β-amyloid protein in an individual, comprising administering an effective amount of a compound or imaging agent described herein; generating an image of a body part or 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).

[0186] 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.

[0187] In some embodiments, compounds are provided that have a binding rate for protein aggregates, such as HTT protein aggregates or β-amyloid protein aggregates, suitable for functioning as imaging agents. Thus, the compounds described herein may be characterized by one or more of: 1) a high affinity for such protein aggregates; 2) a low affinity for adjacent structures; and / or 3) a slow dissociation rate from such protein aggregates. The dissociation rate can be calculated according to the following formula, where A and B refer to the protein aggregate and the imaging agent, and k assn is the association rate constant), the dissociation rate constant k diss It can be expressed as: d[AB] / dt = k assn [A][B] - k diss [AB]

[0188] 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, or any range therebetween. In some embodiments, an effective amount of a compound or imaging agent described herein comprises about 10 mCi.

[0189] Suitable radionuclides that can be incorporated into the compounds described herein include, but are not limited to, 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 The radionuclide incorporated into the compound depends 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: 99m Incorporation of chelated radionuclides, such as Tc, may also be useful. 18 Due to the longer half-life of F, imaging can be performed for a long enough time for a stronger signal to develop. 18 F 11 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.

[0190] In some embodiments, the compounds or imaging agents described herein include 11 C and18 The compound may be labeled with a positron emitter selected from F. 11 The method for introducing C is 11 C] iodomethane or [ 11 Carbon-11 has a half-life of approximately 20 minutes, and thus 11 C typically needs to be produced in an on-site cyclotron, 11 C] can be produced as carbon dioxide. 11 C] Carbon dioxide is a suitable species for direct labeling (generally [ 11 C]iodomethane, and the synthesis of the radiopharmaceutical is completed on-site for use in PET imaging studies after appropriate radiochemical purity and specific activity have been determined. 18 Exemplary methods for introducing F include, but are not limited to, nucleophilic and electrophilic methods. Nucleophilic methods include replacing halides, tosylates, or other leaving groups with labeled cesium fluoride, potassium fluoride, tetrabutylammonium fluoride, tetramethylammonium fluoride, or potassium fluoride kryptofix-222. 18Electrophiles that may be suitable for introducing [F] isotopes include labeled diethylaminosulfur trifluoride (DAST), bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor), N-fluorobenzenesulfonimide (NFSI), N-fluoropyridinium salts, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor), N-fluoropyridinium triflate, xenon fluoride, 2-pyridinesulfonyl fluoride (PyFluor), 3-pyridinesulfonyl fluoride, 4-pyridinesulfonyl fluoride, 4-chloro-2-pyridinesulfonyl fluoride, ethenesulfonyl fluoride, fluoro-benzoiodoxol, p-fluorophenylaminosulfur trifluoride, p-nitrophenylaminosulfur trifluoride, or pentafluorophenylaminosulfur trifluoride. General methods for the introduction of positron emitters are described in the literature (see, for example, Miller et al., Angewandte Chemie International Edition, Vol. 47 (2008), pp. 8998-9033; Jacobson, O. et al., Bioconjugate Chem., Vol. 26 (2015), pp. 1-18; Deng, X. et al., Angewandte Chemie International Edition, Vol. 58 (No. 9), (2019), pp. 2580-2605).

[0191] Fluorine-18 has a half-life of approximately 110 minutes, so [ 18 Synthesis of the [F] radiopharmaceutical does not necessarily have to be performed at the site of a cyclotron or in close proximity to a PET imaging research center. Fluorine-18 is also believed to exhibit favorable nuclear and physical properties, including a high positron decay ratio (97%), a favorable half-life (109.7 minutes), and low positron energy (up to 0.635 MeV). This positron energy can accommodate a short diffusion range in vivo (<2.4 mm), which may provide an excellent resolution limit for PET imaging.

[0192] Methods for performing PET imaging are as described in the Examples herein and as found in the literature. Exemplary studies include "Carbon 11-labeled Pittsburgh compound B and carbon 11-labeled (R)-PK1 1195 positron emission tomographic imaging in Alzheimer's disease," Arch. Neurol. 2009; 66(1): 60-67.

[0193] As will be appreciated, the steps of the methods described herein do not have to be performed a particular number of times or in a particular order. Additional objects, advantages and novel features of the present disclosure will become apparent to those skilled in the art upon examination of the following examples, which are intended to be illustrative and not limiting.

[0194] Indications and Treatment Methods The compounds or imaging agents described herein may be useful for treating a disease or condition mediated at least in part by an aggregation-prone protein. In some embodiments, the compounds or imaging agents described herein are useful for treating a disease or condition mediated at least in part by an HTT protein.

[0195] In some embodiments, treatment of a disease or condition 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 active agents and / or therapies. Thus, in some embodiments, there is provided a method of treating or preventing a disease or condition 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.

[0196] Exemplary diseases and conditions are provided below.

[0197] Huntington's Disease (HD) Huntington's disease (HD) is an inherited 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 may extend 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. The group also includes dentatorubral-pallidoluysian atrophy (DRPLA), spinal-bulbar muscular atrophy (SBMA), and spinocerebellar ataxias (SCAs). In HD, selective neurodegeneration of gamma-aminobutyric acid releasing spiny-projection neurons of 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, memory and / or cognitive impairment.

[0198] The HD protein huntingtin (HTT protein) is a 348 kDa multidomain protein that contains 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 more than 60 repeats of the expansion. It is believed that longer polyQ domains cause conformational changes in the HTT protein that lead to the formation of intracellular aggregates that often appear as nuclear inclusions; however, aggregates can also form outside of 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.

[0199] The parts of the brain most affected by HD, and therefore most likely to contain HTT protein abnormalities, are 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.

[0200] The basal ganglia are a group of subcortical nuclei that are primarily responsible for motor control, as well as other roles such as motor learning, executive function and behavior, and emotion. It is believed that disruption of the basal ganglia reticular system leads to several motor disorders. The 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 as well as interneuron activity, and is ensured by several recurrent or internal basal ganglia circuits. The motor circuit of the basal ganglia has two input points, the striatum and the subthalamic nucleus, and one output point, the internal pallidal segment, which connects to the cortex via the motor thalamus.

[0201] For example, treatment may proceed by degradation of mutant huntingtin (mHTT) by a proteolytic targeting chimera (PROTAC) or bifunctional chimera comprising the compounds described herein. Conjugating compounds that target mHTT to form heterobifunctional compositions is useful for such treatment. Examples of such conjugates are provided in International Application No. WO 2020 / 176424, which is incorporated herein by reference in its entirety. Such conjugates may be represented by the formula WL-ULM [In the formula, W is a compound that targets mutant huntingtin protein (mHTT), such as the compounds described herein; L is a bond or linking moiety optionally substituted with B; B is a moiety that crosses the blood-brain barrier and / or enhances cell permeability; ULM is E3 ubiquitin ligase targeting moiety. wherein L, B, and ULM may be as described in WO 2020 / 176424.

[0202] In some embodiments, W is a moiety of formula X, as described herein.

[0203] In certain embodiments, W is of formula X:

[0204] [ka] [In the formula, Ring A is a 9-membered bicyclic heteroaryl; Ring B is a 6-membered heterocyclyl, a 6-membered oxo-heterocyclyl, or a 6-membered heteroaryl; Ring C is a 6-membered heteroaryl; Z is O, S, NH, or N(C 1~3 alkyl); L is CH 2 , CH(C 1~3 alkyl), C(C 1~3 Alkyl) 2 or C(O); R 1 are cyano, halo, hydroxy, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, deuterated C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, deuterated C 1~6 Haloalkoxy, C 1~6 Alkylthio, C 3~8 Cycloalkyl, heterocyclyl, heteroaryl, amino, alkylamino, dialkylamino, or -O-alkylene-O-SO 2 -R5 and; R 5 is aryl optionally substituted with alkyl; R 2 is absent or is cyano, halo, hydroxy, nitro, C 1~6 Alkyl, C 1~6 Haloalkyl, deuterated C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, deuterated C 1~6 Haloalkoxy, C 1~6 Alkylthio, C 3~8 cycloalkyl, heterocyclyl, heteroaryl, amino, alkylamino, or dialkylamino; R 3 are cyano, halo, hydroxy, nitro, C 1~6 Alkyl, C 1~6 Haloalkyl, deuterated C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, deuterated C 1~6 Haloalkoxy, C 1~6 Alkylthio, C 3~8 cycloalkyl, heterocyclyl, heteroaryl, amino, alkylamino, or dialkylamino; R 4 are cyano, halo, hydroxy, nitro, C 1~6 Alkyl, C 1~6 Haloalkyl, deuterated C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, deuterated C 1~6 Haloalkoxy, C 1~6 Alkylthio, C 3~8 cycloalkyl, heterocyclyl, heteroaryl, amino, alkylamino, or dialkylamino; n1 is 0, 1, or 2; n2 is 0, 1, or 2; R 1 , R 2 , R 3 , or R 4one of which contains a moiety replaceable by L or ULM] or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof; ULM has the formula:

[0205] [ka] [In the formula, W C is CH 2 , C.H.R. E , C=O, SO 2 , NH, or N-alkyl; each X D are independently O, S, and H 2 Selected from; Y A is CH 2 , -C=CR F , NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O, or S; Z A is O, S, or H 2 where X D and Z A Both are H 2 It cannot be; G A and G B are each independently H, R F Alkyl optionally substituted with OH, R F OCOOR E , R F OCONR E R G , R F Optionally substituted with -CH 2 -heterocyclyl, and R F benzyl optionally substituted with; Q A , Q B , Q C , and Q D are each independently F, N, or N-oxide; A is H, alkyl, cycloalkyl, Cl, or F; R E -CONR F R G , -OR F , -NR F R G , -SR F , -SO 2 R F , -SO 2 NR F R G , -CR F R G , -CR F NR F R G , aryl, heteroaryl, optionally substituted alkyl, cycloalkyl, heterocycloalkyl, -P(O)(OR F )(R G ), -P(O)R F R G , -OP(O)(OR F )(R G ), -OP(O)R F R G , Halo, -CF 3 , -CN, -NR F SO 2 NR F R G , -NR F CONR F R G , -CONR F COR G , -NR F C(=N-CN)NR F R G , -C(=N-CN)NR F R G , -NR F C(=N-CN)R G , -NR F C(=C-NO 2 )NR F R G , -SO 2 NR F COR G , -NO 2 , -CO 2 R F, -C(C=N-OR F )R G , -CR F =CR F R G , -CCR F , -S(C=O)(C=NR F )R G ,-SCIENCE FICTION 5 , or -OCF 3 and; R F and R G are each independently a bond, H, N, N-oxide, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, or -C(O)R H wherein alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted; R H is hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; Z B is a functional group or atom, optionally one of which is modified to be covalently attached to formula X. is part of; The point of attachment of W to L-ULM is at any substitutable atom of formula X; The linking moiety has the formula: -G 1 -((CH 2 ) a -G 2 ) c -(CH 2 ) b -G 3 - [In the formula, G 1 , G 2 , and G 3 each independently represents a bond, -NR 28 -, -O-, -S(O) 0~2 -, -NR 28 C(O)-, -C(O)NR 28 -, -NR 28 S(O) 2 -, -S(O) 2 NR 28 -, -CR29 =N-NR 28 -, -NR 28 -N=CR 29 -, -C(O)-, alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene; each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene is independently oxo, halo, C 1~4 Alkyl, C 1~4 Alkoxy and C 1~4 optionally substituted with 1 to 5 substituents independently selected from haloalkyl; Each R 28 are independently hydrogen, C 1~4 Alkyl, C 1~4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; R 29 is C 1~4 Alkyl, C 1~4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; a and b are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8; c is an integer between 0 and 20. of; The linking moiety is, on a substitutable atom, (-G 4 -(CH 2 ) d -G 5 -) e -B and optionally replaced by G 4 and G 5 each independently represents a bond, -NR 28 -, -O-, -S(O) 0~2 -, -NR 28 C(O)-, -C(O)NR 28 -, -NR 28 S(O) 2-, -S(O) 2 NR 28 -, -CR 29 =N-NR 28 -, -NR 28 -N=CR 29 -, -C(O)-, alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene; each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene is independently selected from oxo, halo, C 1~4 Alkyl, C 1~4 Alkoxy and C 1~4 optionally substituted with 1 to 5 substituents independently selected from haloalkyl; d and e are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8; B is a carrier peptide, cholesterol, or a carrier peptide conjugated to cholesterol (e.g., via a linking moiety or covalent bond as described herein), e.g., B can be Angiopep2, ApoE-I, ApoE-II, ApoB, THR, peptide-22, L57, TGN, leptin 30, RVG29, Nipah virus envelope (env.) HR region conjugated to cholesterol, Newcastle disease virus conjugated to cholesterol, or measles virus peptide conjugated to cholesterol; specific examples of B moieties include those in the following table:

[0206] [Table 3]

[0207] In some embodiments, W is a moiety of formula I, formula Ia, or formula Ib; R 1 , R 2 , or R 3 contains a group replaceable by L or ULM.

[0208] Administration of a compound described herein may result in a reduction, e.g., at least a 10% reduction (e.g., at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 100%), in one or more symptoms of a disease or condition described herein. The disease or condition may be a nervous system disorder secondary to a disease, condition, or therapy that has a primary effect outside the nervous system; damage to the nervous system caused by physical, mechanical, or chemical trauma; autoimmune neurodegeneration; neurodegeneration secondary to an infection; and / or ocular neurodegeneration. Symptoms of neurodegeneration include, for example, tremors, bradykinesia, ataxia, loss of balance, depression, cognitive decline, short-term memory loss, long-term memory loss, confusion, personality changes, speech problems, loss of sensation, sensitivity to touch, numbness in the limbs, muscle weakness, muscle paralysis, muscle spasms, muscle cramps, significant changes in eating habits, excessive anxiety or worry, insomnia, delusions, hallucinations, fatigue, back pain, chest pain, indigestion, headache, rapid heart rate, dizziness, blurred vision, shadows or missing areas in vision, metamorphopsia, impairment in color vision, decreased recovery of visual function after exposure to bright light, and loss of visual contrast sensitivity.

[0209] Neurodegenerative diseases are diseases or conditions that impair the function of the nervous system of a subject. Examples of neurodegenerative diseases include, for example, Alexander's disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy's disease, and Krabbe's disease. , kuru, Lewy body dementia, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion disease, Refsum disease, Sandhoff disease, Schilder's disease, subacute combined spinal cord degeneration secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia, spinal muscular atrophy, Steele-Richardson-Olszewski disease, insulin resistance, or tabes dorsalis.

[0210] In some embodiments, the disease or condition is selected from Huntington's disease (HD), dentatorubral-pallidoluysian atrophy, spinal-bulbar muscular atrophy, spinocerebellar ataxia, 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.

[0211] The compounds described herein may inhibit neuronal degeneration when administered to a subject. In some embodiments, inhibiting neuronal degeneration may include inhibiting the degeneration of axons or neurons in a neuron. Such inhibition may involve whole neurons or portions thereof, such as neuronal cell bodies, axons, and dendrites. This may be assessed, for example, by analyzing nervous system function by methods known in the art. Administration of a compound described herein may result in at least a 10% decrease (e.g., at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%) in the number of neurons (or their neuronal bodies, axons, or dendrites) that degenerate in a neuronal population or subject compared to the number of neurons (or their neuronal bodies, axons, or dendrites) that degenerate in a neuronal population or subject to which one or more compounds described herein are not administered.

[0212] Neurons can convey information from tissues and organs to the central nervous system (afferent or sensory neurons) and transmit signals from the central nervous system to effector cells (efferent or motor neurons). Other neurons, designated interneurons, connect neurons within the central nervous system (brain and spinal column). Certain illustrative examples of neuronal types that may be subject to treatment according to the present disclosure include cerebellar granule neurons, dorsal root ganglion neurons, PNS neurons (e.g., sensory neurons), and cortical neurons. Other examples of cell types that may be subject to treatment according to the present disclosure include astrocytes and microglia.

[0213] Additionally, the compounds described herein can be used to prevent or treat memory loss. Types of memory that are affected by loss and thus can be treated by the present disclosure include episodic memory, semantic memory, short-term memory, and long-term memory.

[0214] In some embodiments, the disease or condition is 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 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.

[0215] In some embodiments, the pathological process is associated with or caused by a disease or condition selected from Huntington's disease (HD), dentatorubral-pallidoluysian atrophy, spinal-bulbar muscular atrophy, spinocerebellar ataxia, 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 disease, and spinocerebellar ataxia. 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.

[0216] In some embodiments, the neurodegenerative disease is Huntington's disease.

[0217] Also provided is the use of a compound described herein for the manufacture of a medicament for use in the diagnosis, prevention, or treatment of a disease or condition described herein. For example, the disease or condition can be Huntington's disease.

[0218] Imaging agents and pharmaceutical compositions Imaging agents generally include compounds described herein labeled with a positron-emitting radionuclide. Imaging agents labeled with a positron-emitting radionuclide are generally administered via intravenous injection immediately (e.g., within 1 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. Dosage may vary depending on a variety of factors, including, but not limited to, the association rate of the compound, the amount of emission from the radionuclide used, the half-life of the radionuclide, the part of the body, region of the body, and / or tissue to be imaged, and individual characteristics. One of skill in the art will appreciate that an effective amount will generally be an amount of labeled 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 mass of the labeled compound in an effective amount of imaging agent may be about 0.1 to about 500 mg.

[0219] 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, 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 implant, or via oral or nasal inhalation.

[0220] For PET imaging, administration of the compounds or imaging agents described herein to an individual may be intravenous. The pharmaceutical compositions may take the form of a sterile injectable aqueous or oleaginous suspension. The suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents listed above. The sterile injectable product may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable vehicle, for example a solution in 1,3-butanediol. Among the acceptable vehicles that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as solvents or suspending media. For this purpose, any non-irritating fixed oil may be employed, including synthetic mono- or diglycerides. In addition, 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, with appropriate salts.

[0221] 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 the vehicle, depending on the vehicle and concentration used. Advantageously, adjuvants such as local anesthetics, preservatives and buffers can be dissolved in the vehicle. In most pharmaceutical compositions for parenteral administration, the carrier accounts for at least 90% by weight of the total amount of the composition. In some embodiments, the carrier for parenteral administration is selected from propylene glycol, ethyl oleate, pyrrolidone, ethanol and sesame oil.

[0222] The pharmaceutical composition, e.g., an injectable pharmaceutical composition, can include a cyclodextrin. The cyclodextrin can be, for example, hydroxypropyl cyclodextrin or sulfobutylether cyclodextrin. The cyclodextrin can be, for example, α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin.

[0223] The compounds or imaging agents described herein may be administered via microspheres, liposomes, other microparticulate delivery systems, or sustained release formulations that are 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 techniques and protocols mentioned above and other techniques and protocols that can be used according to 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.

[0224] In some embodiments, the compound or imaging agent described herein is administered as a pharmaceutical composition.Therefore, a pharmaceutical composition is provided that comprises at least one compound or imaging agent described herein together with at least one pharma- ceutically acceptable vehicle selected from carrier, adjuvant, and excipient.The compound or imaging agent of the present disclosure can be formulated into a pharmaceutical composition using techniques known to those skilled in the art.

[0225] 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 the compound or imaging agent.

[0226] Exemplary pharma- ceutically 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 lubricants, 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.

[0227] 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.

[0228] At least one compound or imaging agent described herein in effective concentration is mixed with a suitable pharma- ceutically acceptable vehicle.If the compound or imaging agent shows insufficient solubility, methods 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 cosolvents such as dimethylsulfoxide (DMSO), using surfactants such as TWEEN®, or dissolving in aqueous buffer, for example sodium bicarbonate.

[0229] Upon mixing or addition of the compounds or imaging agents 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 may be determined empirically by methods known in the art.

[0230] The 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 one 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 medicamentically simple and palatable product. In some embodiments, the oral pharmaceutical composition contains 0.1-99% of the compound or imaging agent described herein. In some embodiments, the oral pharmaceutical composition contains at least 5% (by weight) of the compound or imaging agent. Some embodiments contain 25%-50% or 5%-75% of the compound or imaging agent.

[0231] Orally administered pharmaceutical compositions also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups, etc. Suitable pharma- ceutically acceptable carriers 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.

[0232] 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.

[0233] The compounds or imaging agents described herein may be incorporated into oral liquid products such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs. Additionally, pharmaceutical compositions containing the compounds or imaging agents described herein may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid products may 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, which may include edible oils (e.g., almond oil, fractionated coconut oil, silyl esters, propylene glycol, and ethyl alcohol), and preservatives (e.g., methyl or propyl p-hydroxybenzoate, and sorbic acid).

[0234] 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.

[0235] Aqueous suspensions are provided that contain compound or imaging agent in admixture with excipients suitable for producing aqueous suspensions.Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and 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 partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitol replacements, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan replacements.Aqueous suspensions can also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate.

[0236] 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 a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents can be added to provide a palatable oral product. These pharmaceutical compositions can be preserved by the addition of an antioxidant, such as ascorbic acid.

[0237] The pharmaceutical composition may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil (e.g., olive oil or peanut oil), or a mineral oil (e.g., 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 said partial esters with ethylene oxide, such as sorbitan monooleate polyoxyethylene.

[0238] 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.

[0239] Tablets typically contain, as inert diluents, conventional pharma- ceutically acceptable adjuvants, 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; lubricants, such as magnesium stearate, stearic acid and talc. Glidants, 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 driven by secondary considerations, such as taste, cost, and storage stability.

[0240] 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 near the desired local application or at various times to extend the desired effect. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethylcellulose, Eudragit® coatings, waxes and shellac.

[0241] 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.

[0242] The compounds or imaging agents described herein may be administered in the form of suppositories for rectal administration of drugs.These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at normal temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug.Such materials include cocoa butter and polyethylene glycol.

[0243] The compounds or imaging agents described herein may be formulated for local or topical application, e.g., for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions, as well as 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, and the like.

[0244] Topical pharmaceutical compositions comprising at least one compound described herein, or an isotopically labeled analog, pharma- ceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof, may 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.

[0245] 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 that can be used alone or in mixtures with one or more other materials are as follows:

[0246] Representative softening agents 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, dimethylpolysiloxane, diisopropyl sebacic acid, and ethylhexyl stearate. -n-butyl, 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 include propane, butane, isobutane solvents include ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran; humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, and gelatin; and powders include 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.

[0247] The compounds or imaging agents described herein may also be formulated for transdermal administration as a transdermal patch.

[0248] The compounds or imaging agents described herein may also be administered in liposome delivery systems. Liposomes can be classified into small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of amphiphilic molecules, especially phospholipids. Liposome constituents include cholesterol, stearylamine, and / or phosphatidylcholine. Liposomes are suitable for a variety of routes of administration, including topical and injection into various tissues. Thus, intravitreal (e.g., in the treatment of glaucoma), intraperitoneal, intravenous, intravascular, intraarticular, and intramuscular administration of liposomes is contemplated.

[0249] Other pharmaceutical compositions useful for achieving systemic delivery of compound or imaging agent include sublingual, buccal and intranasal dosage forms.Such pharmaceutical compositions typically include soluble filler materials such as sucrose, sorbitol and mannitol, and binders such as one or more of acacia, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose.The glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.

[0250] 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 such as dichlorodifluoromethane or trichlorofluoromethane.

[0251] The pharmaceutical compositions may optionally include an activity enhancer. Activity enhancers may 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.

[0252] The pharmaceutical composition may contain additional active agents, which may be selected from a wide variety of molecules that may function in various ways to enhance the therapeutic effect of the compounds or imaging agents described herein. These optional other active agents, when present, 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.

[0253] The dosage of the compounds or imaging agents described herein will depend on a variety of factors, including, among other considerations, the particular pathological process to be 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. The dosage for a given situation will generally be determined appropriately by the practitioner based on these and other factors.

[0254] The compounds or imaging agents described herein are typically administered in a manner determined by a practitioner, such as a physician, at dosage levels. For example, the compounds or imaging agents may be administered in single or multiple doses, generally at dosage levels of 0.001-100 mg / kg, such as 0.01-100 mg / kg, such as 0.1-70 mg / kg, such as 0.5-10 mg / kg. The doses may be, for example, for once-daily or twice-daily administration. A unit dosage form may generally contain 0.01-1000 mg, such as 0.1-50 mg, of the compounds or imaging agents described herein. For intravenous administration, the compounds or imaging agents may be administered in single or multiple doses, generally at dosage levels of 0.001-50 mg / kg, such as 0.001-10 mg / kg, such as 0.01-1 mg / kg. A unit dosage form may contain, for example, 0.1 to 10 mg of compound or imaging agent.

[0255] Kits and Packaging Also provided herein is a kit comprising the compound described herein and suitable packaging. In certain embodiments, the kit further comprises instructions for use. In some embodiments, the kit comprises a compound or imaging agent described herein and a label and / or instructions for use of the compound in treating an indication, including a disease or condition described herein.

[0256] Also provided herein is an article of manufacture comprising a compound or imaging agent described herein in a suitable container, which may be a vial, bottle, ampoule, pre-filled syringe, and intravenous bag.

[0257] Packaged pharmaceutical compositions are also provided. Such packaged compositions include a pharmaceutical composition comprising 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 disease or condition described herein. The packaged pharmaceutical composition may include prescribing information, for example, to a patient or health care provider, or as a label on the packaged pharmaceutical composition. Prescribing information may include, for example, efficacy, dosage and administration, contraindications, and adverse reaction information regarding the pharmaceutical composition.

[0258] In all of the foregoing, the compounds or imaging agents may be administered alone, as mixtures, or in combination with other active agents.

[0259] 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 disease or condition described herein. For example, the disease or condition may be Huntington's disease.

[0260] Also provided is the use of a compound described herein for the manufacture of an imaging agent for use in the diagnosis, prevention, or treatment of a disease or condition described herein. For example, the disease or condition may be Huntington's disease.

[0261] Combination treatment The methods described herein include methods for detecting, treating or preventing a disease or condition described herein, comprising administering to a subject a compound or imaging agent described herein and one or more additional active agents simultaneously or sequentially. For example, the disease or condition may be Huntington's disease. In methods using simultaneous administration, the agents may be in a combined composition or may be administered separately. When used in combination with one or more additional active agents, the compound or imaging agent described herein may be administered before, simultaneously with, or after administration of the additional active agents. Administration may be by the same route or by different routes.

[0262] Also provided are pharmaceutical compositions comprising a compound or imaging agent described herein and one or more additional active 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 additional active 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. 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.

[0263] Also provided are methods for treating or preventing Alzheimer's disease, including treating 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.

[0264] In some embodiments, the compounds described herein can be administered with an active agent for treating Parkinson's disease, for example, L-dopa, dopamine agonists (e.g., bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphine, and lisuride), dopa decarboxylase inhibitors (e.g., levodopa, benserazide, and carbidopa), and / or MAO-B inhibitors (e.g., selegiline and rasagiline). In some embodiments, the compounds described herein can be administered with an active agent for treating Alzheimer's disease, for example, acetylcholinesterase inhibitors (e.g., donepezil, galantamine, and rivastigmine) and / or NMDA receptor antagonists (e.g., memantine).

[0265] Compound synthesis The compounds described herein can be prepared using the methods disclosed herein and routine variations thereof that are evident 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 typical 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.

[0266] 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 of ordinary skill in the art by routine optimization procedures.

[0267] In addition, 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 certain 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 references cited therein.

[0268] In addition, the compounds described herein may contain one or more asymmetric ("chiral") centers. Thus, if desired, such compounds may 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 included within the scope of the present disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds may be separated, for example, using chiral column chromatography, supercritical fluid chromatography, chiral resolving agents, and the like. When enantiomerically pure or enriched compounds are 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.

[0269] 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 sources, such as Sigma Aldrich, Alfa Aesar, etc. Others can be prepared by procedures or obvious modifications thereof described in standard references 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 edition, 2001) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0270] The terms "solvent", "inert organic solvent" and "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). In general, the term inert, as used herein with respect to a solvent, refers to a material that does not undergo reaction to form the target compound of interest via a carbon-carbon bond forming reaction. Unless otherwise specified, the solvents used in the reactions of the present disclosure are inert organic solvents and the reactions are carried out under an inert gas, preferably nitrogen or argon.

[0271] The term "qs" means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%).

[0272] It is also understood that the addition of any of the substituents in each of the schemes below 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.

[0273] Incorporation of a label into the compounds or imaging agents described herein may be accomplished by reacting a suitable starting material with a reagent that contains a positron-emitting isotope. The methods generally follow the same principles as standard organic chemistry reactions and can be accomplished by any method known to those of skill in the art, including those provided in this disclosure.

[0274] Schemes 1 and 2 provide exemplary synthetic routes 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 from, for example, compound 1 and compound 6, and by attaching the desired substituents using suitable conditions (e.g., nucleophilic addition or cross-coupling).

[0275] In some embodiments, the synthesis of the compounds described herein begins according to Scheme 1.

[0276] [ka]

[0277] In Scheme 1, R 2is as defined herein and X is a halogen, such as bromo, chloro, or iodo. In Scheme 1, pyrimidine-4-carboxylic acid 1 undergoes amide bond formation with pyridinamine compound 2 in the presence of a peptide coupling reagent, such as EDC.HCl, HOBt, HATU, and the like, and a suitable base, such as pyridine, to give a compound of formula 3. Alternatively, pyrimidine-4-carboxylic acid 1 can be converted to the corresponding pyrimidine acyl halide by contacting 1 with a halogenating agent, such as but not limited to phosphorus(V) oxychloride, oxalyl chloride, and the like, and then reacted directly with pyridinamine compound 2 to give a compound of formula 3. Compound 3 is then cyclized to give oxazolopyridine compound 4 by treatment with a base, such as sodium carbonate, under microwave irradiation. The remaining halide on oxazolopyridine compound 4 can be oxidized by Miyaura boration (e.g., palladium-based reagents, such as PdCl 2 (dppf) or any other suitable reagent, bis(pinacolato)diboron, in the presence of a suitable base, such as potassium acetate, can be converted to a hydroxyl group, followed by oxidation of the intermediate boronic ester with sodium perborate tetrahydrate or any other suitable reagent to give compounds of formula 5.

[0278] In some embodiments, the synthesis of the compounds described herein may be carried out according to Scheme 2.

[0279] [ka]

[0280] In Scheme 2, R 1 , R 2 , R 3and n are as defined herein, and X is a halogen, such as bromo, chloro, or iodo. In Scheme 2, the primary alcohol of the pyridine compound of formula 6 is converted to a halide by treatment with, for example, thionyl chloride to give a compound of formula 7. Compounds of formula I, Ia, or Ib can be prepared by the reaction of S between oxazolopyridine compound 5 and pyridine compound 7 in the presence of a suitable base, for example potassium carbonate. N Alternatively, pyridine compound 6 can be reacted directly with oxazolopyridine compound 5 under suitable Mitsunobu reaction conditions (e.g., in the presence of cyanomethyltributylphosphorane, triphenylphosphine and azodicarboxylate, or any other suitable reagent) to give compounds of formula I, Ia, or Ib.

[0281] The synthesis of the compounds described herein can also be carried out by methods described herein or known in the art, for example, the methods described in International Publication No. WO 2016 / 033445.

[0282] Compounds including, but not limited to, Compound 9 18 The synthesis of compounds of Formula I, Ia, or Ib described herein bearing an F-radionuclide may be prepared according to Scheme 3.

[0283] [ka]

[0284] In Scheme 3, R 2 , R 3 and n is as defined herein; R L is substituted with one leaving group (e.g., mesylate, tosylate, or triflate); 1~6 Alkyl, C 1~6 Haloalkyl or deuterated C 1~6 haloalkyl; and R of compound 9 1a is C 1~6 Haloalkyl or deuterated C 1~6haloalkyl, R 1a At least one halo of 18 F. In Scheme 3, the cyclotron-generated 18 The F anion is reacted with compound 8 under phase transfer conditions (e.g., K2,2,2, etc.) in the presence of a base (e.g., potassium carbonate, 2-(tert-butyl)-1,1,3,3-tetramethylguanidine, etc.) to give compound 9 under standard conditions.

[0285] Those skilled in the art will appreciate that any of the compounds described herein can be prepared from starting materials obtained from commercial sources. Alternatively, the synthesis of the compounds described herein can be as described herein or as known to one of skill in the art. EXAMPLES

[0286] The following examples are included to illustrate specific embodiments of the present disclosure. It should be understood by those skilled in the art that the techniques disclosed in the following examples represent techniques that work well in implementing the present disclosure, and therefore can be considered to constitute specific modes for its implementation. However, those skilled in the art should understand in light of the present disclosure that many changes can be made to the specific embodiments disclosed and still obtain the same or similar results without departing from the spirit and scope of the present disclosure.

[0287] 1. General Experimental Procedure 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, or a Bruker DPX 250 MHz spectrometer, or a Bruker AVANCE 300 or Bruker AVANCE 500 spectrometer. 1H 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, or an Isco Combiflash Rf system using appropriately sized pre-packed silica columns and solvents as recorded in the experimental section. Reverse-phase MPLC chromatography was performed on an Isco Combiflash Rf system using appropriately sized pre-packed C18 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 using an Isolute Flash SCX-2 from Biotage, loading samples in methanol and eluting with methanol and then 5% ammonia in methanol.

[0288] 2.Analysis method Acid phase HPLC method Alternatively, HPLC-MS (METCR1410) was performed on a Shimadzu LCMS-2010EV system using a Kinetix Core-Shell C18 reversed-phase column (5 μm, 2.1 × 50 mm) at a column temperature of 40 °C, gradient 5-100% B (A = water / 0.1% formic acid, B = acetonitrile / 0.1% formic acid) for 1.2 min, then 100% B for 0.1 min, injection volume 3 μL, flow rate = 1.2 mL / min. All other aspects of the method were unchanged.

[0289] 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 mm × 100 mm) at a column temperature of 40 °C with a gradient of 5-100% B (A = water / 0.1% formic acid; B = acetonitrile / 0.1% formic acid) 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 range m / z 150-850 using a Waters ZQ with a sampling rate of 2 scans per second. Data were integrated and reported using OpenLynx software.

[0290] Alternatively, UHPLC (METAMRI001) was performed on a Waters Acquity H-Class system using an Acquity UPLC BEH C18 column (1.7 μm, 2.1 × 75 mm) with a gradient of 5 to 100% B (A = water / 0.1% trifluoroacetic acid, B = acetonitrile / 0.1% trifluoroacetic acid) for 6.0 min, followed by 100% B for 2.0 min, flow rate = 0.5 mL / min. UV spectra were recorded at 254 and 215 nm.

[0291] Alternatively, UHPLC (METAMRI002) was performed on a Waters Acquity H-Class system using an Acquity UPLC BEH C18 column (1.7 μm, 2.1 × 75 mm) with a gradient of 5 to 100% B (A = water / 0.1% trifluoroacetic acid, B = acetonitrile / 0.1% trifluoroacetic acid) for 6.0 min, followed by 100% B for 2.0 min, flow rate = 0.4 mL / min at ambient column temperature (approximately 22 °C). UV spectra were recorded at 254 and 215 nm.

[0292] Alternatively, mass spectra and LCMS analyses were obtained using a Waters Acquity SQD (ESI, UP-LCMS) system or an Agilent G6100A SQ LCMS system. All examples exhibit LC purity >95% unless otherwise stated.

[0293] Basic Phase HPLC Method Analytical HPLC-MS (METCR1600) was performed on a Hewlett Packard HPLC system using a Phenomenex Gemini C18 reversed-phase column (3 μm, 2.0 × 100 mm) with a gradient of 5-100% 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, injection volume 3 μL, flow rate = 0.5 mL / min. UV spectra were recorded using a Waters PDA detector at 215 nm. Mass spectra were acquired using a Waters ZQ over the range m / z 150-850 with a sampling rate of 2 scans per second. Data were integrated and reported using OpenLynx software.

[0294] All example compounds exhibit LC purity >95% unless otherwise stated.

[0295] Preparative HPLC method Preparative HPLC separations were performed on a Varian Prep HPLC system using a Varian SD-1 preparative LC pump and a ProStar 325 UV / Vis detector. An XBridge Prep C18 OBD column (5 μm, 19×250 mm) was used and eluted according to the solvent gradient method 2.

[0296] [Table 4]

[0297] Intermediates Intermediate 1: (5-(allyloxy)pyridin-2-yl)methanol

[0298] [ka]

[0299] Step 1: (5-(allyloxy)pyridin-2-yl)methanol A solution of 6-(hydroxymethyl)pyridin-3-ol (100 mg, 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 (166 mg, 1.19 mmol) in water (3.0 mL) and then the solution was heated at 60° C. for 2 h. After this time, the solution was cooled to room temperature and extracted with MTBE (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, CDCl 3 ) 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).

[0300] Intermediate 2: (5-(fluoromethoxy)pyridin-2-yl)methanol

[0301] [ka]

[0302] Step 1: Methylene bis(4-methylbenzenesulfonate) A mixture of silver p-toluenesulfonate (11.5 g, 41.1 mmol) and MeCN (43.4 mL) was treated with diiodomethane (5.00 g, 18.7 mmol) and the mixture was stirred at reflux for 16 h. After this time, the mixture was cooled to room temperature, filtered, and the filter cake was washed with MeCN (3 x 20 mL). The filtrate was concentrated in vacuo. DCM (40 mL) was added to the residue, the suspension was filtered, and the filter cake was washed with DCM (3 x 20 mL). The filtrate was concentrated in vacuo and the resulting residue was recrystallized from EtOH (30 mL). The isolated product was dried in vacuo to give the title compound. 1 H NMR (300 MHz, CDCl 3 ) 7.59 (d, J = 8.4 Hz, 4H), 7.25 (d, J = 8.7 Hz, 4H), 5.81 (s, 2H), 2.45 (s, 6H).

[0303] Step 2: Fluoromethyl 4-methylbenzenesulfonate A mixture of methylene bis(4-methylbenzenesulfonate) (4.09 g, 11.5 mmol) and MeCN (26.7 mL) was treated with 1M TBAF in THF (12.6 mL, 12.6 mmol) and the mixture was stirred at reflux for 2 h. After this time, the solvent was removed in vacuo and the resulting residue was dissolved in EtOAc (40 mL). The solution was washed with brine (40 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by FCC (silica, 0-50% EtOAc in heptane) to give the title compound. 1 H NMR (300 MHz, CDCl 3 ) 7.84 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 5.74 (d, J = 51.0 Hz, 2H), 2.64 (s, 3H).

[0304] Step 3: (5-(fluoromethoxy)pyridin-2-yl)methanol A mixture of 6-(hydroxymethyl)pyridin-3-ol (300 mg, 2.40 mmol), fluoromethyl 4-methylbenzenesulfonate (588 mg, 2.88 mmol), and acetone (9.0 mL) was treated with potassium carbonate (994 mg, 7.19 mmol) and the mixture was heated at 70° C. for 16 h. After this time, the mixture was cooled to room temperature and extracted with DCM (3×40 mL). The combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by FCC (silica, 0-5% MeOH in DCM) to give the title compound. 1 H NMR (300 MHz, DMSO-d 6 ) 8.32 (d, J = 3.0 Hz, 1H), 7.58 (dd, J = 8.7, 2.7 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 5.90 (d, J = 54.0 Hz, 2H), 5.41 (t, J = 5.7 Hz, 1H), 4.52 (d, J = 5.7 Hz, 2H).

[0305] Intermediate 3: 2-((6-(chloromethyl)pyridin-3-yl)oxy)ethyl 4-methylbenzenesulfonate

[0306] [ka]

[0307] Step 1: 2-((6-(hydroxymethyl)pyridin-3-yl)oxy)ethyl 4-methylbenzenesulfonate Ethylene di(p-toluenesulfonate) (3.55 g, 9.59 mmol) was added to a mixture of 6-(hydroxymethyl)pyridin-3-ol (400 mg, 3.20 mmol) and cesium carbonate (3.12 g, 9.59 mmol) in MeCN (40 mL) and the mixture was stirred at 80° C. for 2.5 h. After this time, the reaction mixture was cooled and filtered through diatomaceous earth, and the filter cake was washed with EtOAc (2×50 mL). The filtrate was concentrated in vacuo and the resulting residue was purified by FCC (silica, 0-10% MeOH in DCM) to give the title compound.1 H NMR (300 MHz, CDCl 3 ) 8.13 - 8.12 (m, 1H), 7.82 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 7.8 Hz, 2H), 7.16 - 7.14 (m, 2H), 4.70 (s, 2H), 4.41 - 4.38 (m, 2H), 4.22 - 4.19 (m, 2H), 3.33 (br s, 1H), 2.46 (s, 3H).

[0308] Step 2: 2-((6-(chloromethyl)pyridin-3-yl)oxy)ethyl 4-methylbenzenesulfonate Thionyl chloride (0.208 mL, 2.85 mmol) was added to a solution of 2-((6-(hydroxy-methyl)pyridin-3-yl)oxy)ethyl 4-methylbenzenesulfonate (460 mg, 1.42 mmol) in DCM (9.9 mL) at 0° C. and the solution was stirred at 0° C. for 1 h. After this time, the reaction mixture was poured into water (25 mL) and extracted with DCM (2×25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound. 1 H NMR (300 MHz, CDCl 3 ) 8.13 (d, J = 3.0 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.37 - 7.34 (m, 3H), 7.12 (dd, J = 8.7, 3.0 Hz, 1H), 4.63 (s, 2H), 4.41 - 4.38 (m, 2H), 4.22 - 4.19 (m, 2H), 2.46 (s, 3H).

[0309] Intermediate 4: 2-(chloromethyl)-3-fluoro-5-methoxypyridine

[0310] [ka]

[0311] Step 1: 2-(chloromethyl)-3-fluoro-5-methoxypyridine Thionyl chloride (0.065 mL, 0.89 mmol) was added to a mixture of (3-fluoro-5-methoxy-pyridin-2-yl)methanol (70 mg, 0.45 mmol) in DCM (3.1 mL) and the mixture was stirred at room temperature for 20 minutes. After this time, the mixture was poured into water (25 mL) and extracted with DCM (2×25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound, which was used without purification.

[0312] Method 1 Scheme for method 1

[0313] [ka]

[0314] Step 1: Ethan-1,2-diyl-d 4 Bis(4-methylbenzenesulfonate) p-Toluenesulfonyl chloride (5.77 g, 30.3 mmol) was dissolved in ethylene glycol-d 4 (0.673 mL, 12.1 mmol) and triethylamine (8.41 mL, 60.5 mmol) and the mixture was stirred at room temperature for 16 h. After this time, DCM (40 mL) was added and the mixture was washed with water (100 mL). The aqueous layer was extracted with DCM (100 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by FCC (silica, 0-5% EtOAc in DCM) to give the title compound. 1 H NMR (300 MHz, CDCl 3 ) 7.74 (d, J = 8.4 Hz, 4H), 7.34 (d, J = 7.8 Hz, 4H), 2.46 (s, 6H). MS (ES + ) (M+H) + 375.

[0315] Step 2: 2-Fluoroethyl-1,1,2,2-d 4 4-Methylbenzenesulfonate 1.0 M TBAF in THF (8.97 mL, 8.97 mmol) was dissolved in ethane-1,2-diyl-d 4 Bis(4-methyl-benzenesulfonate) (2.80 g, 7.48 mmol) was added and the mixture was stirred at reflux for 2 h. After this time the mixture was cooled, diluted with DCM (100 mL) and washed with water (40 mL). The aqueous layer was extracted with DCM (100 mL) and the combined organic layers were dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by FCC (silica, 0-100% DCM in heptane) to give the title compound. 1 H NMR (300 MHz, CDCl 3 ) 7.36 (d, J = 8.1 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H), 2.46 (s, 3H).

[0316] Step 3: (5-(2-fluoroethoxy-1,1,2,2-d 4 )Pyridin-2-yl)methanol 2-Fluoroethyl-1,1,2,2-d in MeCN (20.0 mL) 4 A mixture of 4-methylbenzenesulfonate (363 mg, 1.60 mmol), 6-(hydroxymethyl)pyridin-3-ol (200 mg, 1.60 mmol), and cesium carbonate (1.56 g, 4.80 mmol) was stirred at 80° C. for 2.5 h. After this time, the reaction mixture was cooled and filtered through diatomaceous earth. The filter cake was rinsed with EtOAc (2×50 mL) and the filtrate was concentrated in vacuo. The resulting residue was purified by FCC (silica, 0-5% MeOH in DCM) to give the title compound. 1 H NMR (300 MHz, CDCl 3 ) 8.29 (d, J = 2.7 Hz, 1H), 7.29 - 7.19 (m, 2H), 4.72 (s, 2H), 3.39 (br s, 1H).

[0317] Step 4: 2-(chloromethyl)-5-(2-fluoroethoxy-1,1,2,2-d 4 ) Pyridine Thionyl chloride (0.139 mL, 1.91 mmol) was dissolved in DCM (6.7 mL) to give 5-(2-fluoroethoxy-1,1,2,2-dichloromethane). 4 )pyridin-2-yl)methanol (167 mg, 0.953 mmol) and the mixture was stirred at 0° C. for 1 h. After this time, the mixture was poured into water (25 mL), the layers were separated, and the aqueous layer was extracted with DCM (2×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound. 1 H NMR (300 MHz, CDCl 3 ) 8.30 (d, J = 2.7 Hz, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.36 (dd, J = 8.7, 3.0 Hz, 1H), 4.72 (s, 2H).

[0318] Step 5: 6-((5-(2-fluoroethoxy-1,1,2,2-d 4 )pyridin-2-yl)methoxy)-2-(6-methyl-pyrimidin-4-yl)oxazolo[5,4-b]pyridine Potassium carbonate (391 mg, 2.83 mmol) was dissolved in DMF (5.5 mL) with 2-(6-methylpyrimidin-4-yl)oxazolo[5,4-b]pyridin-6-ol (215 mg, 0.942 mmol) and 2-(chloromethyl)-5-(2-fluoroethoxy-1,1,2,2-d 4 ) pyridine (182 mg, 0.942 mmol) and the mixture was stirred at room temperature for 16 h and at 40° C. for 5 h. After this time, the mixture was cooled, mixed with water (40 mL) and extracted with EtOAc (3×20 mL) and DCM (20 mL). The combined organic layers were dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by FCC (silica, 0-5% MeOH in DCM) to give the title compound.

[0319] Example 1-1: 6-((5-(2-fluoroethoxy-1,1,2,2-d 4 )pyridin-2-yl)methoxy)-2-(6-methyl-pyrimidin-4-yl)oxazolo[5,4-b]pyridine 1 H NMR (300 MHz, CDCl 3 ) 9.32 (d, J = 1.2 Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.30 (d, J = 2.7 Hz, 1H), 8.10 (d, J = 0.6 Hz, 1H), 7.76 (d, J = 3.0 Hz, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.31 - 7.26 (m, 1H), 5.27 (s, 2H), 2.70 (s, 3H). 19 F NMR (282 MHz, CDCl 3 ) -225.80. Tr(METAMRI001) = 3.38 min, (ES + ) (M+H) + 386.2, 99%.

[0320] The following additional compounds were prepared by Method 1:

[0321] Example 1-2: 2-((6-(((2-(6-methylpyrimidin-4-yl)oxazolo[5,4-b]pyridin-6-yl)oxy)-methyl)pyridin-3-yl)oxy)ethyl 4-methylbenzenesulfonate

[0322] [ka]

[0323] 1 H NMR (300 MHz, DMSO-d 6) 9.31 (d, J = 1.2 Hz, 1H), 8.29 (d, J = 2.7 Hz, 1H), 8.20 (d, J = 3.0 Hz, 1H), 8.10 (s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 2.7 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.17 (dd, J = 8.7, 3.0 Hz, 1H), 5.25 (s, 2H), 4.42 - 4.39 (m, 2H), 4.24 - 4.21 (m, 2H), 2.70 (s, 3H), 2.46 (s, 3H). Tr(METAMRI001) = 4.05 minutes, (ES + ) (M+H) + 534.3, 99%.

[0324] Example 1-3: 6-((3-fluoro-5-methoxypyridin-2-yl)methoxy)-2-(6-methylpyrimidin-4-yl)oxazolo[5,4-b]pyridine

[0325] [ka]

[0326] 1 H NMR (500 MHz, CDCl 3 ) 9.31 (d, J = 1.0 Hz, 1H), 8.29 (d, J = 3.0 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 8.10 (s, 1H), 7.88 (d, J = 2.5 Hz, 1H), 7.01 (dd, J = 11.0, 2.5 Hz, 1H), 5.31 (d, J = 2.0 Hz, 2H), 3.89 (s, 3H), 2.70 (s, 3H). 19 F NMR (282 MHz, CDCl 3 ) -122.91. Tr(METAMRI001) = 3.72 min, (ES + ) (M+H) +368.1, 99%.

[0327] Example 1-4: 2-((6-(((2-(6-methylpyrimidin-4-yl)oxazolo[5,4-b]pyridin-6-yl)oxy)methyl)pyridin-3-yl)oxy)-ethyl-1,1,2,2-d 4 4-Methylbenzenesulfonate

[0328] [ka]

[0329] 1 H NMR (500 MHz, CDCl 3 ) 9.31 (d, J = 1.0 Hz, 1H), 8.29 (d, J = 3.0 Hz, 1H), 8.20 (d, J = 3.0 Hz, 1H), 8.09 (d, J = 0.5 Hz, 1H), 7.82 (dd, J = 8.5, 2.0 Hz, 2H), 7.75 (d, J = 2.5 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.17 (dd, J = 8.5, 3.0 Hz, 1H), 5.25 (s, 2H), 2.70 (s, 3H), 2.45 (s, 3H). Tr(METAMRI001) = 4.37 min, (ES + ) (M+H) + 538.3, 99%.

[0330] Method 2 Scheme for method 2

[0331] [ka]

[0332] Step 1: 2-Methylpyrimidine-4-carbonyl chloride To a solution of 2-methylpyrimidine-4-carboxylic acid (5.0 g, 36.2 mmol) in anhydrous dichloromethane (100 mL) was added N,N-dimethylformamide (0.2 mL) and the reaction was cooled to 0° C. Oxalyl chloride (5.7 mL, 66.2 mmol) was added dropwise and the reaction was allowed to warm to room temperature over 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated in vacuo and co-distilled with dichloromethane (3×30 mL) to give the title compound. Tr(METCR1410) (MeOH) = 0.64 min, (ES + ) (M+H) + 158, 85% (as methyl ester).

[0333] Step 2: N-(5-bromo-2-chloropyridin-3-yl)-2-methylpyrimidine-4-carboxamide To a stirred solution of 2-methylpyrimidine-4-carbonyl chloride (5.7 g, 36.2 mmol) in pyridine (40 mL) at 0° C. was added 5-bromo-2-chloropyridin-3-amine (7.9 g, 38.0 mmol). The mixture was stirred at room temperature overnight. Water was added to the mixture. The precipitate was filtered and washed with water to give the title compound. 1 H NMR (500 MHz, DMSO-d 6 ) 10.64 (s, 1H), 9.09 (d, J = 5.0 Hz, 1H), 8.82 (d, J = 2.3 Hz, 1H), 8.46 (d, J = 2.3 Hz, 1H), 7.98 (d, J = 5.0 Hz, 1H), 2.80 (s, 3H). Tr(METCR1410) = 1.23 minutes, (ES + ) (M+H) + 327, 329, 96%,

[0334] Step 3: 4-{6-bromo-[1,3]oxazolo[5,4-b]pyridin-2-yl}-2-methylpyrimidine In duplicate: To a solution of N-(5-bromo-2-chloropyridin-3-yl)-2-methylpyrimidine-4-carboxamide (400 mg, 1.22 mmol) in anhydrous N,N-dimethylformamide (12 mL) in a microwave vessel was added sodium carbonate (129 mg, 1.22 mmol). The reaction vessel was sealed and irradiated at 160° C. for 2 h. The combined cooled reaction mixture was concentrated in vacuo and the residue was triturated from water. The crude residue was purified by column chromatography (0-100% ethyl acetate in heptane followed by 0-25% methanol in dichloromethane) to give the title compound. 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.04 (d, J = 5.1 Hz, 1H), 8.79 (d, J = 2.2 Hz, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.17 (d, J = 5.1 Hz, 1H), 2.79 (s, 3H). Tr(METCR1410) = 1.01 minutes, (ES + ) (M+H) + 291, 293, 82%.

[0335] The recovered starting material was split (200 mg and 330 mg) and the reaction was repeated at larger dilutions (10 mL and 15 mL N,N-dimethylformamide, respectively). The reactions were heated for 7 and 2 h, respectively, and purified as above to give the title compounds. 1 H NMR (500 MHz, DMSO-d 6 ) 9.13 - 8.95 (m, 1H), 8.78 (d, J = 2.2 Hz, 1H), 8.66 (d, J = 2.2 Hz, 1H), 8.16 (d, J = 5.1 Hz, 1H), 2.78 (s, 3H). Tr(METCR1410) = 1.01 min, (ES + ) (M+H) + 291, 293, 63%.

[0336] Step 4: 2-(2-methylpyrimidin-4-yl)-[1,3]oxazolo[5,4-b]pyridin-6-ol 4-{6-bromo-[1,3]oxazolo[5,4-b]pyridin-2-yl}-2-methylpyrimidine (170 mg, 0.58 mmol) was dissolved in dioxane (10 mL) and N 2 The mixture was degassed for 10 min under a stream of water. Potassium acetate (143 mg, 1.46 mmol), bis(pinacolato)diboron (163 mg, 0.64 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex (PdCl 2 (dppf).DCM) (43 mg, 0.06 mmol) was added and the reaction was heated at 100° C. under nitrogen for 2.5 h. After complete conversion to the boronic ester / acid, the reaction mixture was cooled to room temperature. Water (3 mL) was added followed by sodium perborate tetrahydrate (108 mg, 0.7 mmol) and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water (5 mL) and the resulting precipitate was filtered and dried to give the title compound. Tr(METCR1410) = 0.77 min, (ES + ) (M+H) + 229, 59%.

[0337] Step 5: {4-{6-[(5-methoxypyridin-2-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridin-2-yl}-2-methylpyrimidine To a pressure tube was added 2-(2-methylpyrimidin-4-yl)-[1,3]oxazolo[5,4-b]pyridin-6-ol (59%, 74 mg, 0.19 mmol), (5-methoxypyridin-2-yl)methanol (26.62 mg, 0.19 mmol), and CMBP (0.06 mL, 0.21 mmol) in toluene. The vessel was sealed and heated at 100° C. for 2 h. Additional (cyanomethylene)tributylphosphorane (CMBP) (0.10 mL, 0.38 mmol) was added and the reaction mixture was stirred at 110° C. for 7 h. The cooled reaction mixture was concentrated in vacuo and triturated with 1:1 ethyl acetate:heptane, 3:1 ethyl acetate:heptane, and finally 100% ethanol to give the title compound.

[0338] Example 2-1: {4-{6-[(5-methoxypyridin-2-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridin-2-yl}-2-methylpyrimidine 1 H NMR (500 MHz, DMSO-d 6 ) 9.01 (d, J = 5.1 Hz, 1H), 8.33 (t, J = 3.2 Hz, 2H), 8.20 - 8.10 (m, 2H), 7.58 (d, J = 8.5 Hz, 1H), 7.46 (dd, J = 8.6, 2.9 Hz, 1H), 5.29 (s, 2H), 3.85 (s, 3H), 2.78 (s, 3H). Tr(MET-uHPLC-AB-101) = 2.28 min, (ES + ) (M+H) + 350.2, 96%

[0339] Method 3 Scheme for method 3

[0340] [ka]

[0341] Step 1: 6-(2-fluoroethoxy)pyrimidine-4-carboxylic acid To a stirred solution of 2-fluoroethanol (0.62 mL, 10.7 mmol) in DMF (20 mL) at 0° C. was added sodium hydride (60%, 428 mg, 10.7 mmol). The reaction was stirred for 5 min and ethyl 6-chloropyrimidine-4-carboxylate (1.0 g, 5.4 mmol) was added at 0° C. The reaction mixture was warmed to room temperature and stirred for 4 h. The reaction mixture was quenched with water (15 mL) and diluted with ethyl acetate (15 mL). The organic layer was separated and washed with brine (10 mL). The aqueous phase was acidified using 2 M HCl and extracted with chloroform:isopropanol (3:1, 5×10 mL). The combined organics were dried (Na 2 SO 4 ), filtered and concentrated in vacuo to give the title compound. 1H NMR (250 MHz, DMSO-d 6 ) 8.91 (d, J = 1.0 Hz, 1H), 7.40 (d, J = 1.0 Hz, 1H), 4.93 - 4.71 (m, 2H), 4.70 - 4.55 (m, 2H). Tr(METCR1410) = 0.37 min, (ES + ) (M+H) + 187, 100%.

[0342] Step 2: N-(5-bromo-2-hydroxypyridin-3-yl)-6-(2-fluoroethoxy)pyrimidine-4-carboxamide EDC.HCl (745 mg, 3.9 mmol) was added to a solution of 3-amino-5-bromopyridin-2-ol (490 mg, 2.6 mmol) and 6-(2-fluoroethoxy)pyrimidine-4-carboxylic acid (482 mg, 2.6 mmol) in pyridine (20 mL), and the resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was then diluted with water (10 mL), and the resulting precipitate was collected, washed with water and heptane, and dried under vacuum to give the title compound. 1 H NMR (500 MHz, DMSO-d 6 ) 12.52 (s, 1H), 10.58 (s, 1H), 9.01 (d, J = 1.0 Hz, 1H), 8.46 (d, J = 2.6 Hz, 1H), 7.51 (dd, J = 7.4, 1.8 Hz, 2H), 4.87 - 4.74 (m, 2H), 4.74 - 4.65 (m, 2H). Tr(METCR1410) = 1.05 min, (ES + ) (M+H) + 357, 359, 76%.

[0343] Step 3: 4-{6-bromo-[1,3]oxazolo[5,4-b]pyridin-2-yl}-6-(2-fluoroethoxy)pyrimidine A mixture of triphenylphosphine (725 mg, 2.76 mmol), hexachloroethane (818 mg, 3.45 mmol), and triethylamine (0.77 mL, 5.53 mmol) in DCM (25 mL) was stirred for 5 min, after which N-(5-bromo-2-hydroxypyridin-3-yl)-6-(2-fluoroethoxy)pyrimidine-4-carboxamide (94%, 525 mg, 1.38 mmol) was added. The reaction mixture was stirred at room temperature for 20 h. After standing overnight, a precipitate was observed. The precipitate was collected and dried under vacuum to give the title compound. Tr(METCR1600) = 1.05 min, (ES + ) (M+H) + 339, 341, 88%.

[0344] Step 4: 2-[6-(2-fluoroethoxy)pyrimidin-4-yl]-[1,3]oxazolo[5,4-b]pyridin-6-ol In duplicate: 4-{6-bromo-[1,3]oxazolo[5,4-b]pyridin-2-yl}-6-(2-fluoroethoxy)pyrimidine (195 mg, 0.58 mmol) was dissolved in THF (10 mL) in a pressure tube and cooled to 37° C. with N 2 The mixture was degassed for 10 minutes under reflux. Potassium acetate (141 mg, 1.44 mmol), bis(pinacolato)diboron (161 mg, 0.63 mmol), and PdCl 2 (dppf) (42 mg, 0.06 mmol) was added and the reaction vessel was sealed and heated at 80° C. under nitrogen for 16 h. The reaction mixtures were combined and cooled to room temperature. Water (5 mL) was added and the resulting precipitate was removed by filtration. Sodium perborate tetrahydrate (212 mg, 1.38 mmol) was added to the filtrate and the reaction mixture was stirred at room temperature for 4.5 h. The reaction mixture was concentrated in vacuo and water (10 mL) was added. The precipitate was collected by vacuum filtration and further dried under vacuum at 40° C. for 2 h to give the title compound. 1 H NMR (500 MHz, DMSO-d 6) 10.29 (s, 1H), 9.02 (s, 1H), 8.06 (s, 1H), 7.69 (s, 2H), 4.86 (s, 1H), 4.75 (d, J = 11.8 Hz, 2H), 4.68 (s, 1H). 0.89 minutes, (ES + ) (M+H) + 277, 74%.

[0345] Step 5: 4-(2-fluoroethoxy)-6-{6-[(5-methoxypyridin-2-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyrimidine To a pressure tube was added 2-[6-(2-fluoroethoxy)pyrimidin-4-yl]-[1,3]oxazolo[5,4-b]pyridin-6-ol (74%, 223 mg, 0.6 mmol), (5-methoxypyridin-2-yl)methanol (91 mg, 0.66 mmol), and CMBP (0.19 mL, 0.72 mmol) in toluene (5 mL). The vessel was sealed and heated at 100 °C for 5 h. The reaction mixture was re-treated with (5-methoxypyridin-2-yl)methanol (91 mg, 0.66 mmol) and CMBP (0.19 mL, 0.72 mmol) and stirred at 100 °C for an additional 15 h. The cooled reaction mixture was concentrated in vacuo and purified by column chromatography (0-20% methanol in DCM) followed by preparative HPLC to give the title compound.

[0346] Example 3-1: 4-(2-fluoroethoxy)-6-{6-[(5-methoxypyridin-2-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyrimidine 1 H NMR (500 MHz, DMSO-d 6) 9.04 (d, J = 1.0 Hz, 1H), 8.33 - 8.31 (m, 2H), 8.16 (d, J = 2.8 Hz, 1H), 7.72 (d, J = 1.0 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.45 (dd, J = 8.6, 2.9 Hz, 1H), 5.28 (s, 2H), 4.89 - 4.66 (m, 2H), 4.78 - 4.74 (m, 2H), 3.84 (s, 3H). + ) (M+H) + 398, 99%.

[0347] Method 4 Scheme for method 4

[0348] [ka]

[0349] Steps 1 and 2: N-(5-bromo-2-chloropyridin-3-yl)-6-methylpyrimidine-4-carboxamide To a solution of 5-bromo-2-chloropyridin-3-amine (1.61 g, 7.8 mmol) in pyridine (25 mL) was added 6-methylpyrimidine-4-carboxylic acid (1.07 g, 7.8 mmol) at room temperature. The reaction mixture was then cooled to 0° C. and phosphorus(V) oxychloride (1.44 ml, 15.5 mmol) was added dropwise over 10 minutes. The reaction mixture was stirred at 0° C. for 1 hour and then quenched with water (10 mL) at 0° C. and then concentrated in vacuo. The residue was triturated with water to give the title compound. 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.64 (s, 1H), 9.31 (d, J = 1.2 Hz, 1H), 8.79 (d, J = 2.3 Hz, 1H), 8.46 (d, J = 2.3 Hz, 1H), 8.10 (s, 1H), 2.65 (s, 3H). Tr(METCR1410) = 1.24 minutes, (ES+ ) (M+H) + 327, 329, 100%.

[0350] Step 3: 4-{6-bromo-[1,3]oxazolo[5,4-b]pyridin-2-yl}-6-methylpyrimidine In quadruple: To a solution of N-(5-bromo-2-chloropyridin-3-yl)-6-methylpyrimidine-4-carboxamide (400 mg, 1.22 mmol) in anhydrous N,N-dimethylformamide (15 mL) in a microwave vessel was added sodium carbonate (129 mg, 1.22 mmol). The vessel was sealed and irradiated at 160° C. for 4 h. The cooled reaction mixture was concentrated in vacuo and the residue was triturated with water. The crude residue was purified by column chromatography (0-100% EtOAc in heptane followed by 0-20% methanol in DCM) to give the title compound. 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.32 (d, J = 1.2 Hz, 1H), 8.78 (d, J = 2.2 Hz, 1H), 8.66 (d, J = 2.2 Hz, 1H), 8.32 - 8.26 (m, 1H), 2.65 (s, 3H). Tr(METCR1410) = 1.01 minutes, (ES + ) (M+H) + 291, 293, 66%.

[0351] Step 4: 2-(6-Methylpyrimidin-4-yl)-[1,3]oxazolo[5,4-b]pyridin-6-ol 4-{6-bromo-[1,3]oxazolo[5,4-b]pyridin-2-yl}-6-methylpyrimidine (66%, 163 mg, 0.37 mmol) was dissolved in dioxane (10 mL) in a pressure tube and cooled to 37° C. 2 The mixture was degassed for 10 minutes at RT. Potassium acetate (91 mg, 0.92 mmol), bis(pinacolato)diboron (103 mg, 0.41 mmol), and PdCl 2(dppf) (27 mg, 0.04 mmol) was added and the reaction vessel was sealed and heated at 100° C. under nitrogen for 4 h. After complete conversion to the boronic ester / boronic acid, the reaction mixture was cooled to room temperature, water (3 mL) was added and the resulting precipitate was collected and removed. Sodium perborate tetrahydrate (78 mg, 0.50 mmol) was added to the filtrate and the reaction mixture was stirred at room temperature for 17 h. The reaction mixture was quenched with water (5 mL) and concentrated in vacuo. The residue was diluted with water (3 mL) and the product was collected and dried by vacuum filtration to give the title compound. Tr(METCR1410) = 0.81 min, (ES + ) (M+H) + 229, 43%.

[0352] Step 5: 4-{6-[(5-methoxypyridin-2-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridin-2-yl}-6-methylpyrimidine To a pressure tube was added 2-(6-methylpyrimidin-4-yl)-[1,3]oxazolo[5,4-b]pyridin-6-ol (47%, 70 mg, 0.14 mmol), (5-methoxypyridin-2-yl)methanol (40 mg, 0.29 mmol), and CMBP (0.08 mL, 0.29 mmol) in toluene (5 mL). The vessel was sealed and heated at 75° C. for 8 h. The reaction mixture was retreated with (5-methoxypyridin-2-yl)methanol (40 mg, 0.29 mmol) and CMBP (0.08 mL, 0.29 mmol) and heated at 75° C. for 10 h. The reaction mixture was retreated again with (5-methoxypyridin-2-yl)methanol (40 mg, 0.29 mmol) and CMBP (0.08 mL, 0.29 mmol) and heated at 75° C. for 3 h. The cooled reaction mixture was concentrated in vacuo and triturated with 3:1 EtOAc:heptane followed by 3:1 ethanol:water. The material was purified twice by column chromatography (0-10% methanol in DCM, then separately 0-10% EtOAc in heptane followed by 0-10% methanol in DCM). Trituration with ethanol and preparative HPLC (high pH) gave the title compound.

[0353] Example 4-1: 4-{6-[(5-methoxypyridin-2-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridin-2-yl}-6-methylpyrimidine 1 H NMR (500 MHz, DMSO-d 6 ) 9.29 (d, J = 1.2 Hz, 1H), 8.35 - 8.30 (m, 2H), 8.26 (s, 1H), 8.16 (d, J = 2.7 Hz, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.46 (dd, J = 8.6, 3.0 Hz, 1H), 5.29 (s, 2H), 3.84 (s, 3H), 2.64 (s, 3H). Tr(MET-uHPLC-AB-101) = 2.31 min, (ES + ) (M+H) + 350, 100%.

[0354] Method 5 Scheme of method 5

[0355] [ka]

[0356] Step 1: N-(5-bromo-2-hydroxypyridin-3-yl)-6-methylpyrimidine-4-carboxamide A mixture of 3-amino-5-bromopyridin-2-ol (1.37 g, 7.25 mmol) in DCM (109 mL) was treated with 6-methylpyrimidine-4-carboxylic acid (1.00 g, 7.25 mmol), the mixture was cooled to 0° C. and treated with pyridine (2.92 mL, 36.2 mmol) and EDC (2.08 g, 10.9 mmol). The mixture was stirred at 0° C. for 10 minutes and at room temperature for 16 hours. After this time, the mixture was concentrated in vacuo. The resulting residue was triturated with DCM (10 mL) and the product was collected by filtration and dried in vacuo to provide the title compound. 1 H NMR (300 MHz, DMSO-d 6) 12.56 (br s, 1H), 10.63 (s, 1H), 9.27 (d, J = 1.2 Hz, 1H), 8.45 (d, J = 2.7 Hz, 1H), 8.06 (d, J = 0.6 Hz, 1H), 7.51 (d, J = 2.7 Hz, 1H), 2.63 (s, 3H).

[0357] Step 2: 6-Bromo-2-(6-methylpyrimidin-4-yl)oxazolo[5,4-b]pyridine A mixture of triphenylphosphine (3.56 g, 13.6 mmol) and hexachloroethane (2.01 g, 8.49 mmol) in DCM (79 mL) was treated dropwise with triethylamine (3.78 mL, 27.2 mmol) over 15 min. The mixture was stirred at room temperature for 10 min. N-(5-bromo-2-hydroxypyridin-3-yl)-6-methylpyrimidine-4-carboxamide (1.05 g, 3.40 mmol) was then added and the mixture was stirred at room temperature for 16 h. After this time, the mixture was washed with saturated aqueous sodium bicarbonate (100 mL) and water (100 mL). The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by FCC (silica, 0-5% MeOH in DCM) to give the title compound. 1 H NMR (300 MHz, DMSO-d 6 ) 9.34 (d, J = 0.9 Hz, 1H), 8.56 (d, J = 2.1 Hz, 1H), 8.33 (d, J = 2.1 Hz, 1H), 8.13 (d, J = 0.6 Hz, 1H), 2.72 (s, 3H).

[0358] Step 3: 2-(6-methylpyrimidin-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazolo[5,4-b]pyridine 6-Bromo-2-(6-methylpyrimidin-4-yl)oxazolo[5,4-b]pyridine (350 mg, 1.20 mmol), bis(pinacolato)diboron (458 mg, 1.80 mmol), potassium acetate (295 mg, 3.01 mmol), PdCl2 A mixture of dppf (88 mg, 0.12 mmol) and THF (8.8 mL) was heated at 90° C. for 7 h. After this time, the mixture was cooled and treated with water (5 mL). The product was collected by filtration, washed with water (3 mL) and dried in vacuo to give the title compound. 1 H NMR (300 MHz, DMSO-d 6 ) 9.32 (d, J = 1.2 Hz, 1H), 8.71 (d, J = 1.2 Hz, 1H), 8.50 (d, J = 1.5 Hz, 1H), 8.32 (d, J = 0.6 Hz, 1H), 2.65 (s, 3H), 1.36 (s, 12H).

[0359] Step 4: 2-(6-Methylpyrimidin-4-yl)oxazolo[5,4-b]pyridin-6-ol A mixture of 2-(6-methylpyrimidin-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-oxazolo[5,4-b]pyridine (435 mg, 1.29 mmol) in THF (22.0 mL) was treated with a mixture of sodium perborate tetrahydrate (237 mg, 1.54 mmol) in water (22.0 mL) and the mixture was stirred at room temperature for 1 h. After this time, the mixture was treated with saturated aqueous ammonium chloride solution (10 mL). The volatiles were removed in vacuo and the resulting aqueous suspension was filtered. The collected material was washed with water (15 mL), dried in vacuo, and purified by FCC (silica, 0-5% MeOH in DCM) to give the title compound. 1 H NMR (300 MHz, DMSO-d 6 ) 10.29 (s, 1H), 9.28 (d, J = 1.2 Hz, 1H), 8.24 (d, J = 0.9 Hz, 1H), 8.07 (d, J = 2.7 Hz, 1H), 7.69 (d, J = 2.7 Hz, 1H), 2.63 (s, 3H).

[0360] Step 5: (5-(2-fluoroethoxy)pyridin-2-yl)methanol A mixture of 6-(hydroxymethyl)pyridin-3-ol (270 mg, 2.16 mmol) and potassium carbonate (447 mg, 3.23 mmol) in anhydrous MeCN (6 mL) was treated with 1-bromo-2-fluoroethane (0.32 mL, 4.3 mmol) and the resulting reaction mixture was heated in a sealed tube at 70° C. for 24 h. After this time, the reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The organic layers were combined, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to provide the title compound, which was used in the next step without purification. 1 H NMR (300 MHz, DMSO-d 6 ) 8.22 (dd, J = 2.7, 0.6 Hz, 1H), 7.45 - 7.37 (m, 2H), 5.32 (t, J = 5.7 Hz, 1H), 4.85 - 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). MS (ES + ) (M+H) + 172.

[0361] Step 6: 6-((5-(2-fluoroethoxy)pyridin-2-yl)methoxy)-2-(6-methylpyrimidin-4-yl)oxazolo[5,4-b]pyridine CMBP (0.23 mL, 0.88 mmol) was added to a mixture of 2-(6-methylpyrimidin-4-yl)oxazolo[5,4-b]pyridin-6-ol (100 mg, 0.438 mmol) and (5-(2-fluoroethoxy)pyridin-2-yl)methanol (113 mg, 0.657 mmol) in anhydrous toluene (5 mL) and the mixture was heated at 100° C. for 2 h. After this time, the mixture was cooled to room temperature and adsorbed onto silica gel with 1:1 MeOH / DCM (100 mL) and purified by FCC (silica, 0-10% MeOH in DCM). The product was triturated with acetonitrile to give the title compound.

[0362] Example 5-1: 6-((5-(2-fluoroethoxy)pyridin-2-yl)methoxy)-2-(6-methylpyrimidin-4-yl)oxazolo[5,4-b]pyridine 1 H NMR (500 MHz, DMSO-d 6 ) 9.29 (d, J = 1.0 Hz, 1H), 8.35 (d, J = 3.0 Hz, 1H), 8.32 (d, J = 2.5 Hz, 1H), 8.25 (s, 1H), 8.15 (d, J = 2.5 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.50 (dd, J = 8.5, 3.0 Hz, 1H), 5.30 (s, 2H), 4.82 - 4.81 (m, 1H), 4.73 - 4.71 (m, 1H), 4.39 - 4.37 (m, 1H), 4.33 - 4.31 (m, 1H), 2.64 (s, 3H). 19 F NMR (282 MHz, DMSO-d 6 ) -222.33. Tr(METAMRI002) = 3.00 min, (ES + ) (M+H) + 382.2, 98%.

[0363] The following additional compounds were prepared by Method 1:

[0364] Example 5-2: 6-((5-(allyloxy)pyridin-2-yl)methoxy)-2-(6-methylpyrimidin-4-yl)oxazolo[5,4-b]pyridine

[0365] [ka]

[0366] 1 H NMR (500 MHz, DMSO-d 6) 9.29 (d, J = 0.9 Hz, 1H), 8.33 - 8.32 (m, 2H), 8.25 (d, J = 0.3 Hz, 1H), 8.15 (d, J = 1.5 Hz, 1H), 7.56 (d, J = 5.1 Hz, 1H), 7.46 (dd, J Tr(METAMRI002) = 13.03 minutes, (ES + ) (M+H) + 376.1, 99%.

[0367] Example 5-3: 6-((5-(fluoromethoxy)pyridin-2-yl)methoxy)-2-(6-methylpyrimidin-4-yl)oxazolo[5,4-b]pyridine

[0368] [ka]

[0369] 1 H NMR (500 MHz, DMSO-d 6 ) 9.29 (d, J = 1.0 Hz, 1H), 8.45 (d, J = 1.5 Hz, 1H), 8.34 (d, J = 2.5 Hz, 1H), 8.25 (s, 1H), 8.16 (d, J = 3.0 Hz, 1H), 7.66 (d, J = 1.5 Hz, 2H), 5.94 (d, J = 54.0 Hz, 2H), 5.34 (s, 2H), 2.64 (s, 3H). 19 F NMR (282 MHz, DMSO-d 6 ) -151.59. Tr(METAMRI002) = 12.49 min, (ES + ) (M+H) + 368.1, 98%.

[0370] Method 6 Scheme of method 6

[0371] [ka]

[0372] 6-((5-(2-fluoroethoxy-1,1,2,2-d 4 )pyridin-2-yl)methoxy)-2-(6-methylpyrimidin-4-yl)oxazolo[5,4-b]pyridine (Example 1-1) To a stirred mixture of potassium fluoride (0.00011 g, 0.0019 mmol), 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (K222, 0.00418 g, 0.011 mmol), and 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (BTMG, 0.0019 g, 0.011 mmol) in dimethyl sulfoxide (0.35 mL) was added 2-((6-(((2-(6-methylpyrimidin-4-yl)oxazolo[5,4-b]pyridin-6-yl)oxy)methyl)pyridin-3-yl)oxy)ethyl-1,1,2,2-d 4 4-Methylbenzenesulfonate (Example 1-4) (0.00199 g, 0.00370 mmol) was added and the mixture was stirred at 100° C. for 30 min. After this, the reaction mixture was cooled to room temperature, mixed with formic acid (0.1 mL), injected through a syringe filter (0.2 μm) onto an XBridge C18 column (5 μm ODB, 19×250 mm) and eluted with 22% CAN in water (0.1% formic acid v / v) for 30 min (20 mL / min). The fractions collected between 19.87 and 21.32 min were concentrated and eluted with 6-((5-(2-fluoroethoxy-1,1,2,2-d 4 )pyridin-2-yl)methoxy)-2-(6-methylpyrimidin-4-yl)oxazolo[5,4-b]pyridine: 1 H NMR (500 MHz, DMSO-d 6) δ 9.29 (s, 1H), 8.35 (d, J = 2.9 Hz, 1H), 8.32 (d, J = 2.7 Hz, 1H), 8.25 (s, 1H), 8.15 (d, J = 2.7 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.50 (dd, J = 8.6, 2.9 Hz, 1H), 5.29 (s, 2H), 2.63 (s, 3H); MS (ESI) m / z 386 [M + H] + ; HPLC (Phenomenex Luna C18(2), 5 μm, 4.6 × 150 mm), 5–90% ACN in water (0.1% TFA v / v), 20 min (1.15 mL / min), t R = 8.28 min, >99% (AUC) at 254 and 215 nm.

[0373] Biological assays Exon 1-Q46 radioligand binding assay For radioligand binding assays (RBA), MBP-HTT(1-89)Q46-His(6x) ("exon1-Q46") protein was produced based on a previous publication (Scherzinger et al., Cell, vol. 90, pp. 549-558, Aug. 8, 1997). For the experiments, 30 μM MBP-exon1-Q46 was diluted with 150 μg / mL thrombin and 2 mM CaCl in assay buffer (150 mM NaCl, 50 mM Tris pH 8.0). 2The aggregates were incubated with exon 1-Q46 for 16 hours at 37°C. The aggregated exon 1-Q46 was pelleted by centrifugation at 13,000 rpm for 5 minutes 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 the RBA, exon 1-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 minutes at room temperature. Ligand was then added at 50 μL / well and incubated at 37°C for 60 minutes. The final assay concentrations were 1 μM to 30 pM test compound, 1 μM exon 1-Q46 protein (equivalent monomer concentration), and 0.3 nM ligand [ 3 H 3 The antibody was 5'-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 200 μL PBS using a Filtermate harvester. Filter plates were dried at 55° C. for 1 hour before sealing the plates back with foil and adding 30 μL / well of scintillation fluid (Packard MicroScint 40), incubating for 15 minutes in the dark, and counting 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 H 3 IC was normalized to 0% inhibition and 100% inhibition using [(5-methoxypyridin-2-yl)methoxy]-2-(pyrazin-2-yl)benzo[d]oxazole (100% inhibition). 50 Values ​​were calculated using normalized replicate data and four variables in the global fit (upper, lower, slope, IC 50 ) was determined using the S-order inhibition model.

[0374] The results for various example compounds were as provided in the table below (+++<100nM; ++100-500nM; +>500nM; ND: Undetermined):

[0375] [Table 5]

[0376] Deuterium effects on imaging and bone uptake in a mouse model A total of 61 wild-type (WT) and 68 heterozygous (HET) Q175DN mice aged between 3 and 9 months were included in the study. Dynamic μPET / CT imaging ( 18 90 min for F-labeled compound 1-1) was performed in HET Q175DN mice and WT littermates.

[0377] Dynamic PET scan MicroPET / CT imaging was performed on two Siemens Inveon PET-CT scanners (Siemens Preclinical Solution, USA). Animals (both wild type (WT) and HET Q175DN mice carrying one copy of the expanded human HTT exon-1 gene) were positioned side-by-side on the scanner bed such that the animal's heart was within the field of view of the scanner. Anesthesia was induced by inhalation of isoflurane (5% for induction, 1.5–2% for maintenance during preparation and scanning) supplemented with oxygen. After induction, a catheter was inserted into the tail vein of all mice for intravenous (i.v.) bolus injection of the tracer, and the mice were positioned on the scanner bed. Respiration was constantly monitored during the entire scan period using a Monitoring Acquisition Module (Minerve, France). The core body temperature of the animals was maintained using a warm airflow.

[0378] At the beginning of a 120 min (for proof of concept) or 90 min (for cross-sectional studies) dynamic microPET scan, mice were injected with a bolus of radioactive tracer at 12 s intervals (1 mL / min) using an automated pump (Pump 11 Elite, Harvard Apparatus, USA). To obtain good image quality, the tracer was injected with as high an activity as possible, while the non-radioactive dose was kept as low as possible. Overall, HET Q175DN animals were injected with a bolus of 6.8 ± 2.9 MBq, whereas WT littermates were injected with a bolus of 7.0 ± 1.9 MBq. PET data were acquired in list mode. After the microPET scan, a 10 min 80 kV / 500 μA CT scan was performed for attenuation and scatter correction.

[0379] PET Imaging Acquired PET data were reconstructed into 45 or 39 frames (depending on scan duration) of increasing length (12 x 10 s, 3 x 20 s, 3 x 30 s, 3 x 60 s, 3 x 150 s, and 21 or 15 x 300 s) using list-mode iterative reconstruction with a proprietary spatially-varying resolution modeling with a 3D ordered subset expectation maximization (OSEM 3D) algorithm with 8 iterations and 16 subsets. Normalization, dead-time, random, attenuation, and CT-based attenuation corrections were applied. PET image frames were reconstructed into 0.776 x 0.776 x 0.796 mm2. 3The images were reconstructed on a 128 × 128 × 159 grid with voxels. For arbitrary region-based analysis, image analysis was performed with PMOD 3.6 software (Pmod Technologies, Zurich, Switzerland). Spatial normalization of the PET / CT images was performed through exact matching of the Waxholm template of the CT and PET images to the CT images. Time-activity curves (SUV TAC) of different regions (striatum, motor cortex, cerebellum, thalamus, and hippocampus) were extracted from the images. The kinetic data were investigated for different models (1TCM, 2TCM, 3TCM, and Logan linear model) and then finally fitted by a two-tissue compartment model (2TCM) and the total volume of distribution (V ) was calculated using an image-derived input function (IDIF) based on 90 min of data. T ) was calculated. The input function was obtained from whole blood activity derived from PET images by placing a volume of interest (50% of maximum based on threshold) in the left ventricular lumen.

[0380] analysis Pharmacokinetic modeling was performed for regional quantification. 18 To define the optimal method for PET imaging using F-labeled compound 1-1 as a tracer, we performed a parallel evaluation of different kinetic models. 18 The uptake rate (Ki(IDIF)) of F-labeled compound 1-1 (3sTCM) was calculated using the image-derived input function (IDIF) (not shown).

[0381] In vivo radiometabolite profiles were determined in plasma and brain of 9-month-old Q175DN mice (n=3-6 per genotype and time point) at 5, 15, 30, 45, 60, and 90 min post-injection. No brain-penetrating radiometabolite species were observed. Comparative studies at the 3-month age point with comparator compounds were performed (n=18-20 per genotype) (not shown).

[0382] Average of HET and WT mice at 60–90 min 18F-labeled compound 1-1 SUV images were determined. As expected, SUV images 60–90 min post-injection showed elevated values ​​in HET compared to WT.

[0383] Radioactive metabolite analysis revealed a favorable plasma profile with no obvious brain penetrating species. Significant differences between genotypes at 9 months of age could be measured in all relevant regions. Injection mass doses of less than 0.8 μg / kg were found to be feasible. Test-retest variability was moderate, with intra-animal variability noted.

[0384] In 3-month-old mice, compared to a control compound, 18 F-labeled compound 1-1 showed higher discrimination.

[0385] Using a similar method, the fluorine-18 compound was 18 The SUV of F-labeled Compound 1-1 and Compound 5-1 bone uptake was measured. A graph of the bone uptake SUV results is shown in Figure 1, while the PET images for 40-60 min, 60-90 min, and 90-120 min are provided in Figure 2. The images were overlaid onto an MRI mouse brain template for anatomical localization. Based on the results, 18 It can be seen that F-labeled compound 1-1 provided superior PET imaging resolution due to reduced cleavage of the terminal fluoride in vivo in subject animals.

[0386] PET Imaging Examples The following example illustrates an exemplary, non-limiting procedure that may be utilized when performing a PET imaging study on an individual in a clinical setting. The individual is unmedicated or pre-medicated with an unlabeled compound. The individual may fast prior to PET imaging and is allowed to have water ad libitum. A 20G 2-inch intravenous catheter is inserted into the contralateral ulnar vein for administration of the imaging agent.

[0387] A human subject is placed in the PET camera and administered a tracer dose of the imaging agent via an intravenous catheter. Arterial or venous blood samples are obtained at appropriate time intervals during the PET scan to analyze and quantify the proportion of unmetabolized compound in plasma. Images are acquired for up to 120 minutes. Within 10 minutes of 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 compound (or other intervention compounds) that may have been administered prior to the PET tracer.

[0388] Tomographic images are obtained by image reconstruction. Regions of interest (ROIs) are set on the reconstructed images, for example, to determine the distribution of imaging agents. Regions of interest in brain images may include, for example, the striatum, cerebellum, or basal ganglia. The imaging agent uptake over time in these regions may be used to generate time activity curves (TACs). Data can be expressed as activity per unit time per unit volume (e.g., μCi / cc / mCi injected dose) or activity per unit volume. TAC data can be processed by various methods known in the art to obtain quantitative parameters, such as binding potential (BP). For further description of imaging procedures, see, for example, Waxman AD et al., Society of Nuclear Medicine Procedure Guideline for FDG PET Brain Imaging, ver.1.0, (February 8, 2009).

[0389] 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 disclosure belongs.

[0390] The disclosure illustratively described herein can be suitably implemented without any element or elements, or limitation or limitations not specifically disclosed herein. Thus, for example, terms such as "comprising", "including", "containing" and the like should be interpreted openly and without limitation. Furthermore, the terms and expressions used herein are used as terms of description and not of limitation, and in the use of such terms and expressions, there is no intention to exclude the equivalents of the illustrated and described features or portions thereof, but it is recognized that various modifications are possible within the scope of the present disclosure.

[0391] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, as if each was individually incorporated by reference. In case of conflict, the present specification, including definitions, will control.

Claims

1. Formula I: 【Chemistry 1】 [In the formula, R 1 is C 1～6 Alkyl, C 2～6 Alkenyl, C 1～6 Haloalkyl, deuterated C 1～6 Haloalkyl, C 1～6 Alkoxy, deuterated C 1～6 Haloalkoxy, or -O-alkylene-O-SO 2 -R 5 and; R 5 is aryl optionally substituted with alkyl; R 2 does not exist or C 1～6 Alkyl, C 1～6 Haloalkyl, deuterated C 1～6 Haloalkyl, C 1～6 Haloalkoxy or deuterated C 1～6 haloalkoxy; R 3 Halo, C 1～6 Alkyl or C 1～6 is haloalkyl; n is 0, 1, or 2. or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

2. Formula II: 【Chemistry 2】 2. The compound of claim 1, or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

3. Formula III: 【Chemistry 3】 2. The compound of claim 1, or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

4. Formula IV: 【Chemistry 4】 [In the formula, m is 0, 1, or 2; 11 and each R 12 are independently selected from hydrogen and deuterium, and at least one R 11 or R 12 is deuterium] 2. The compound of claim 1, or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

5. Formula V: 【Chemistry 5】 [In the formula, m is 0, 1, or 2; 11 and each R 12 are independently selected from hydrogen and deuterium, and at least one R 11 or R 12 is deuterium] 2. The compound of claim 1, or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

6. Formula VI: 【Chemistry 6】 [In the formula, m is 0, 1, or 2; 11 and each R 12 are independently selected from hydrogen and deuterium, and at least one R 11 or R 12 is deuterium] 2. The compound of claim 1, or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

7. Formula VII: 【Chemistry 7】 [In the formula, m is 0, 1, or 2; 11 and each R 12 are independently selected from hydrogen and deuterium, and at least one R 11 or R 12 is deuterium] 2. The compound of claim 1, or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

8. R 1 But deuterated C 1～6 Haloalkyl or deuterated C 1～6 2. The compound of claim 1 which is a haloalkoxy.

9. R 1 But deuterated C 1～6 2. The compound of claim 1 which is a haloalkoxy.

10. R 1 Ga-O-CD 2 -CD 2 2. The compound of claim 1, wherein:

11. Each R 11 and each R 12 5. The compound of claim 4, wherein is deuterium.

12. R 2 But, C 1～6 Alkyl or C 1～6 2. The compound of claim 1 which is a haloalkoxy.

13. R 2 C 1～6 2. The compound of claim 1, wherein the compound is alkyl.

14. 2. The compound of claim 1, wherein n is 0.

15. R 3 The compound of claim 1, wherein is fluoro.

16. A compound selected from the compounds of Table 1, optionally labeled with a positron emitting isotope, or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

17. The compound of claim 1, wherein the compound is labeled with a positron-emitting isotope.

18. The compound is 11 C. 13 N, 15 O, and 18 18. The compound of claim 17, containing a positron emitting isotope selected from F.

19. 20. An imaging agent comprising the compound of claim 17, or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

20. 20. A method of detecting the presence or absence of an aggregation-prone protein in an individual comprising administering to the individual an effective amount of a compound of claim 17 or an imaging agent of claim 19 and generating an image of a body part or region of the individual.

21. 21. The method of claim 20, wherein generating an image of a body part or region of an individual comprises generating an image and detecting the presence or absence of aggregation-prone proteins in the image.

22. 22. The method of claim 21, wherein the protein prone to aggregation is huntingtin protein (HTT protein).

23. 23. The method of claim 22, wherein the HTT protein is found in the basal ganglia.

24. 21. The method of claim 20, wherein the presence or absence of protein aggregates corresponds to the presence or absence of a neurodegenerative disease.

25. 25. The method of claim 24, wherein the neurodegenerative disease is selected from Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, prion diseases, and spinocerebellar ataxias.

26. 26. The method of claim 25, wherein the neurodegenerative disease is Huntington's disease (HD).

27. 21. The method of claim 20, wherein the effective amount of the compound or imaging agent comprises from about 0.1 to about 20 mCi.

28. 28. The method of claim 27, wherein the effective amount of the compound or imaging agent comprises about 10 mCi.

29. 21. The method of claim 20, wherein 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.

30. 30. The method of claim 29, wherein generating an image comprises PET imaging.

31. 23. The method of claim 22, wherein the HTT protein is present as an oligomer or aggregate, or a combination thereof.

32. The method of claim 22, wherein the HTT protein is a mutant.

33. 21. The method of claim 20, wherein the body part or region is the head, spine, limb, thorax, or abdomen.

34. 21. The method of claim 20, wherein the body part or body region is the brain.

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