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

Abstract

Provided are certain compounds and imaging agents, compositions thereof, and methods of their use that are useful for detecting diseases or conditions associated with protein aggregation, particularly huntingtin protein aggregation. [Formula 1] TIFF2023530089000159.tif35147

Description

[Technical Field]

[0001] Cross-reference to related patent applications This application claims priority to U.S. Provisional Patent Application No. 63 / 037,751, filed June 11, 2020, which is incorporated herein by reference for all purposes.

[0002] Provided herein are 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 measurement of molecular and cellular mechanisms throughout the body in preclinical and clinical settings. Such measurements have expanded diagnostic utility, and their use to assess treatment response and aid drug development is rapidly expanding. The introduction of high-resolution molecular imaging techniques is seen by many experts as a major breakthrough.

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

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

[0006] Huntington's disease (HD) is a hereditary, 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 triplet repeat within exon-1 of the huntingtin gene (HTT). The resulting polyglutamate domain expansion induces misfolding and conformational changes in the mutant huntingtin (mHTT) protein, potentially leading to the formation of protein aggregates. HD has a worldwide prevalence of 5-10 cases per 100,000, making it the most common inherited and monogenic neurodegenerative disorder.

[0007] As with other medical conditions, treatment of HD ideally begins at or before the earliest signs of disease. Therefore, early indicators of disease onset and reliable pharmacodynamic biomarkers of disease progression are highly desirable. Summary of the Invention [Problem to be solved by the invention]

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

[0009] The present invention relates to compounds useful for imaging huntingtin protein.

[0010] Some embodiments provide compounds of formula I' as described herein, optionally labeled with one or more radioisotopes. In some embodiments, the compound of formula I' is: 11 C. 13 N, 15 O, and 18and F. In some embodiments, an imaging agent is provided comprising a compound of Formula I', or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0011] Some embodiments provide compounds of formula I as described herein, optionally labeled with one or more radioisotopes. In some embodiments, the compound of formula I is 11 C. 13 N, 15 O, and 18 It contains one or more positron-emitting radioisotopes selected from F.

[0012] In some embodiments, an imaging agent is provided comprising a compound of Formula I, or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0013] 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.

[0014] Also provided are methods of producing a diagnostic image, e.g., a positron emission tomography (PET) image, in an individual, comprising administering an effective amount of a compound described herein or an imaging agent comprising a compound described herein, and producing an image of a body part or region of the individual.

[0015] In some embodiments, a compound or imaging agent is provided for use in producing a diagnostic image in an individual, the use comprising administering to the individual an effective amount of a compound or imaging agent as described herein and producing an image of a body part or body region of the individual.

[0016] In some embodiments, there is provided a compound or imaging agent for use as described herein, wherein generating an image of a body part or region of an individual comprises generating an image and detecting the presence or absence of an aggregation-prone protein in the image. In some embodiments, there is provided a compound or imaging agent for use as described herein, wherein the aggregation-prone protein is huntingtin protein (HTT protein). In some embodiments, there is provided a compound or imaging agent for use as described herein, wherein the HTT protein is found in the basal ganglia.

[0017] 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.

[0018] In some embodiments, provided are compounds or imaging agents for the uses described herein, wherein the neurodegenerative disease is selected from Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, prion diseases, and spinocerebellar ataxias. In some embodiments, provided are compounds or imaging agents for the uses described herein, wherein the neurodegenerative disease is Huntington's disease (HD).

[0019] In some embodiments, there is provided a compound or imaging agent for the uses 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 the uses described herein, wherein an effective amount of the imaging agent comprises about 10 mCi.

[0020] In some embodiments, there is provided a compound or imaging agent for the uses 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 the uses described herein, wherein generating an image comprises PET imaging.

[0021] 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.

[0022] In some embodiments, there is provided a compound or imaging agent for the uses 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 the uses described herein, wherein the body part or body region is the brain. DETAILED DESCRIPTION OF THE INVENTION

[0023] The following description describes exemplary embodiments of the present technology, but it should be recognized that such description is not intended as a limitation on the scope of the present invention, but rather is provided as a description of exemplary embodiments.

[0024] 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.

[0025] A compound described herein refers to a compound of any formula described herein, including a compound of Formula I', Formula I, Formula Ia, Formula IIa, Formula IIb, Formula IIc, Formula IId, or an isotopically labeled analogue, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers thereof, or a compound described anywhere herein, including the Examples, or a compound of Table 1A or Table 1B, 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.

[0026] A dash ("-") that is not between two letters or two symbols is used for a substituent to indicate a point of attachment to the parent structure. For example, -C(O)NH2 is attached to the parent structure through a carbon atom. A dash before or at the end of a chemical group is for convenience; chemical groups can be depicted with or without one or more dashes without losing their usual meaning. A wavy or dashed line drawn through a bond in a structure indicates a specified point 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.

[0027] 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.

[0028] Reference herein to "about" a value or parameter includes (and describes) embodiments that are directed to the value or parameter itself. 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. Also, the term "about X" includes the reference to "X." Additionally, the singular forms "a" and "the" include plural references 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.

[0029] "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 1~4Examples 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 specific 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" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0030] Alternative chemical names known to those skilled in the art can be used in place of the terms provided herein. For example, divalent groups, such as divalent "alkyl" groups, divalent "aryl" groups, etc., can also be referred to as "alkylene" or "arylene" groups, respectively. Also, unless expressly indicated otherwise, when combinations of groups are referred to herein as a single moiety, e.g., arylalkyl or aralkyl, the last-mentioned group contains the atom that connects that moiety to the rest of the molecule.

[0031] "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 2~4 Alkenyl refers to an alkyl group having an alkenyl group. Examples of alkenyl groups include, for example, ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl), and isoprenyl.

[0032] "Alkynyl" refers to an alkyl 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 The term "alkynyl" also includes those groups having one triple bond and one double bond.

[0033] "Alkoxy" refers to the group "alkyl-O-". Examples of 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.

[0034] "Alkylamino" refers to an "alkyl-NH-" group. Examples of alkylamino groups include, for example, methylamino, ethylamino, iso-propylamino, tert-butylamino, and n-hexylamino. "Dialkylamino" refers to a "(alkyl)2N-" group. Examples of dialkylamino groups include, for example, dimethylamino, diethylamino, (iso-propyl)(methyl)amino, (n-pentyl)(tert-butyl)amino, and di-n-hexylamino.

[0035] "Alkylthio" refers to the group "alkyl-S-". "Alkylsulfinyl" refers to the group "alkyl-S(O)-". "Alkylsulfonyl" refers to the group "alkyl-S(O)2-". "Alkylsulfonylalkyl" refers to -alkyl-S(O)2-alkyl.

[0036] "Acyl" is -C(O)R y group (in the formula, R yrefers to hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of acyl include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0037] "Amide" is -C(O)NR y R z "C-amido" group, which refers to the group -NR y C(O)R z An "N-amido" group refers to a 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 and (a) together form a cycloalkyl or heterocyclyl, each of which may be optionally substituted as defined herein.

[0038] "Amino" is -NR y 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 is optionally substituted as defined herein. In some embodiments, "amino" refers to an NH group.

[0039] "Amidino" is -C(NR y )(NR z 2) Group (in the formula, R y and R zare independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0040] "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 group 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.

[0041] "Arylalkyl" or "aralkyl" refers to the group "aryl-alkyl-".

[0042] "Carbamoyl" is -OC(O)NR y R z The group refers to the "O-carbamoyl" group and the -NR y C(O)OR z An "N-carbamoyl" group refers to a group where 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.

[0043] "Carboxyl ester" or "ester" refers to the -OC(O)R x and -C(O)OR x ,(where Rx is alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0044] "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 3~6 Cycloalkyl). 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 a fused aryl ring, regardless of attachment to the rest of the molecule. Furthermore, 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 when there are two positions on the carbon atom for substitution in the parent structure. A cycloalkyl may be optionally substituted at the carbon atom of the bond to the parent structure.

[0045] "Cycloalkoxy" refers to the group "-O-cycloalkyl".

[0046] "Cycloalkylalkyl" refers to the group "cycloalkyl-alkyl-".

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

[0048] "Imino" is -C(NR y )R z group (in the formula, R y and R z and each independently refer to hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0049] "Imide" is -C(O)NR y C(O)R z group (in the formula, R y and R z and each independently refer to hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0050] "Halogen" or "halo" refers to a substituent atom in Group VIIA of the periodic table, for example, fluoro, chloro, bromo, or iodo.

[0051] "Haloalkyl" refers to an unbranched or branched alkyl group, as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms, up to and including all hydrogen atoms, have been replaced with 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 need not, be the same halogen. Perhaloalkyl groups are haloalkyl groups in which all hydrogen substituents have been replaced with halogen. 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.

[0052] "Haloalkoxy" refers to an alkoxy group as defined above in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms, up to and including all hydrogen atoms, have been replaced with a halogen.

[0053] "Hydroxyalkyl" refers to an alkyl group, as defined above, in which one or more (eg, 1 to 6 or 1 to 3) hydrogen atoms have been replaced with hydroxy groups.

[0054] "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 groups, 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 -, -NRy C(O)-, -O-, -S-, -S(O)-, -S(O)2-, etc. (wherein R y is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which is optionally substituted as defined herein. Examples of heteroalkyl groups include, for example, ethers (e.g., -CHOCH, -CH(CH)OCH, -CHCHOCH, -CHCHOCH, -CHCHOCHCHOCH, etc.), thioethers (e.g., -CHSCH, -CH(CH)SCH, -CHCHSCH, -CHCHSCHCHSCH, etc.), sulfones (e.g., -CHS(O)CH, -CH(CH)S(O)CH, -CHCHS(O)CH, -CHCHS(O)CHCHOCH, etc.), and aminoalkyls (e.g., -CHNR y CH3, -CH(CH3)NR y CH3, -CH2CH2NR y CH3, -CH2CH2NR y CH2CH2NR y CH3, etc., where R y is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which is optionally substituted as defined herein. As used herein, heteroalkyl includes 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.

[0055] "Heteroaryl" refers to an aryl group in which one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur, and which may contain 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 1~20heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3~12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3~8Heteroaryl) and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, independently selected from nitrogen, oxygen, and sulfur. In certain instances, heteroaryl includes 5-10, 5-7, or 5-6 membered ring systems having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 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, and isoindolyl. Examples 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 single or multiple fused rings containing at least one heteroatom, regardless of attachment 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.

[0056] "Heteroarylalkyl" refers to the group "heteroaryl-alkyl-".

[0057] "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 form 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, and spiro-heterocyclyl groups. Heterocyclyls may be monocyclic or polycyclic, and polycyclic rings may be fused, bridged, or spiro. Regardless of the enumerated substituents, a heterocyclyl may also include one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O) groups, unless otherwise specified. - ) moieties. Heterocyclyl can be attached via a carbon atom or a heteroatom, where valence allows. Furthermore, the term heterocyclyl encompasses any ring system containing a non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring regardless of attachment to the rest 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 system having 3 to 14 ring atoms, 3 to 10 ring atoms, 3 to 6 ring atoms, or 5 to 6 ring atoms, and / or 2 to 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 groups may contain 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, and octahydroisoindolyl. 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 "spiroheterocyclyl." 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. When there are two carbon atom positions available for substitution in the parent structure, heterocyclyl as a substituent may include spiroheterocyclyl. Examples of bridged heterocyclyl rings include, but are not limited to, 2,5-diazabicyclo[2.2.1]heptane and 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, and 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 to 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.

[0058] "Heterocyclylalkyl" refers to the group "heterocyclyl-alkyl-".

[0059] "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.

[0060] "Sulfonyl" is -S(O)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.

[0061] "Sulfinyl" is -S(O)R y group (in the formula, R yrefers to 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.

[0062] "Sulfonamide" is -SO2NR y R z and -NR y SO2R z group (in the formula, R y and R z and each independently refer to hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0063] The term "optionally" or "optionally" means 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 an unsubstituted or substituted group.

[0064] As used herein, the term "substituted" means that any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms have been replaced with a non-hydrogen group, such as, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, arylalkyl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH, =NNH, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)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).

[0065] In certain embodiments, "substituted" means that one or more (e.g., 1 to 5 or 1 to 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)2R g , -OS(=O) 1-2 R g , -S(=O) 1-2 OR g , -NR g S(=O) 1-2 NR g R h , =NSO2R g , =NOR g , -S(=O) 1-2 NR g R h , -SF5, or -SCF3. In certain embodiments, "substituted" also refers to a group in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms have been replaced with -C(=O)R g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g , or -CH2SO2NR 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.

[0066] Polymers or similar indefinite structures arrived at by defining a substituent with an infinite number of additional substituents (e.g., a substituted aryl having 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 expressly stated, 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 impermissible 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.

[0067] 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.

[0068] Any compound or structure given herein is intended to represent unlabeled forms of the compound as well as "isotopically enriched analogs." Isotopically enriched forms of a compound may also be referred to as "labeled." Isotopically enriched analogs have the structure shown 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., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17O. 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 radioactive isotopes, e.g., 3 H, 18 F, 11 C, and 14 C and the like are included in this 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.

[0069] The term "isotopically enriched analog" includes "deuterated analogs" of the compounds described herein, in which one or more hydrogens, e.g., hydrogens on carbon atoms, have been replaced with deuterium. Such compounds can exhibit increased resistance to metabolism and thus can be useful for increasing the half-life of any compound when administered to mammals, particularly humans. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds can be synthesized by means well known in the art, e.g., by utilizing starting materials in which one or more hydrogens have been replaced with deuterium.

[0070] Deuterium-labeled or substituted therapeutic compounds of the present disclosure can have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, e.g., deuterium, can result in certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dose requirements, and / or improved therapeutic index. Isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent and following the procedures disclosed in the schemes described below or in the examples and preparations. Isotopically labeled compounds of the present disclosure and their pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, and mixtures of stereoisomers can generally be prepared by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent and following the procedures disclosed in the schemes described below or in the examples and preparations. Where a compound is described as a deuterated analog, the compound can be depicted with deuterium as a substituent.

[0071] The concentration of such heavy isotopes, particularly deuterium, 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," the position is considered to have hydrogen and its isotopes at their natural abundance.

[0072] 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.

[0073] Also provided are isotopically enriched analogs, pharmaceutically 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.

[0074] 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. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" of the compounds described herein include, for example, acid addition salts obtained by interacting a compound having a basic functional group with an acid, and base addition salts 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-toluenesulfonic 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 alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(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., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl) cycloalkylamines include salts of mono-, di-, or tricycloalkylamines (i.e., NH(cycloalkyl), HN(cycloalkyl), N(cycloalkyl)), mono-, diaryl-, or triarylamines (i.e., NH(aryl), HN(aryl), N(aryl)), 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(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0075] Some compounds described herein may exist as tautomers. For example, if a compound is depicted as containing an amide, the compound may also exist as an imidic acid tautomer; 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 the nature of the equilibrium between the 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.

[0076] The compounds described herein may contain asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, which can be defined in terms of absolute stereochemistry as (R)- or (S)-, or (D)- or (L)- for 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, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from appropriate optically pure precursors or racemic resolution (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). Where 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.

[0077] "Stereoisomer" refers to one of a series of compounds composed of the same atoms joined by the same bonds but with different three-dimensional structures. Various stereoisomers and mixtures thereof are intended to include "enantiomers," which refer to stereoisomeric compounds that are non-superimposable mirror images of one another. "Diastereomers" are one of a series of stereoisomers with at least two asymmetric atoms that are not mirror images of each other.

[0078] A "prodrug" is any molecule that releases a parent drug in vivo, presumably due to activity by the compounds described herein, when such prodrug is administered to a mammalian subject. Prodrugs may be forms of the compounds described herein that have 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 by routine manipulation or in vivo. Prodrugs include compounds described herein in which a hydroxy, amino, carboxyl, or sulfhydryl group in the compounds described herein is bonded to any group that can be cleaved in vivo to regenerate the free hydroxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl), and the like, of hydroxy functional groups in the compounds described herein. The preparation, selection, and use of prodrugs are discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series; "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985; and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is incorporated herein by reference in its entirety.

[0079] In some embodiments, the term "neurodegenerative disease" refers to a disease or condition that impairs the function of a subject's nervous system. Examples of neurodegenerative diseases include those described herein.

[0080] The methods described herein can be applied to cell populations in vivo or ex vivo. "In vivo" means within a living individual, such as 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 the disclosed compounds for a given indication, cell type, individual, and other parameters. Information gleaned from such use can be used clinically for experimental purposes or to design 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 those of skill in the art. Selected compounds can be further characterized to determine safety or tolerated doses in human or non-human subjects. Such properties can be determined using methods commonly known to those skilled in the art.

[0081] The above-listed terms also include in vitro and ex vivo methods.

[0082] As used herein, the terms "group," "moiety," "radical," "substituent," and "fragment" are synonymous and are intended to indicate a portion of a molecule that can be attached to another portion of the molecule, for example, via a designated point of attachment or bond.

[0083] 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, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof. For example, an active agent may be an anti-neurodegenerative therapeutic agent.

[0084] The term "effective amount" refers to an amount of a compound, e.g., as described herein, sufficient to bring about a desired response in an individual or patient. In the context of the use of an imaging agent, an effective amount may be the amount required to produce an image having diagnostic or therapeutic utility. The term "therapeutically effective amount" refers to an amount effective, when administered to a human or non-human patient, to confer a therapeutic benefit, such as amelioration of symptoms, delay of disease progression, or prevention of disease; for example, a therapeutically effective amount may be an amount sufficient to reduce the symptoms of a disease described herein. A (therapeutically) effective amount may vary depending on the subject and disease or condition being treated, the subject's weight and age, the severity of the disease or condition, and the mode of administration, and can be readily determined by one of ordinary skill in the art.

[0085] 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.

[0086] The term "protein aggregates," as used herein, refers to aggregation of proteins, which may be, for example, insoluble fibrillar amyloid comprising misfolded HTT protein molecules ("HTT protein aggregates") or misfolded β-amyloid protein molecules ("β-amyloid aggregates"). An "aggregation-prone protein" is a protein that, in its wild-type or mutant form, is capable of forming such aggregates.

[0087] The term "imaging agent," as used herein, refers to a compound described herein that is labeled with one or more positron-emitting isotopes or radionuclides, or a composition comprising the labeled compound. The positron-emitter-labeled compound need only be enriched with a detectable isotope to an extent that allows detection using techniques appropriate for the particular application.

[0088] 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.

[0089] The term "positron-emitting radionuclide," as used herein, refers to a radionuclide in which protons within the nucleus of the radionuclide emit positrons and electron neutrinos (ν e β refers to radioactive isotopes that exhibit a particular type of radioactive decay called β decay, in which they are converted into neutrons while emitting positrons. Some examples of positron-emitting radionuclides include: 15 O. 13 N, 11 C. 18 F, 76 Br and 124 Contains I.

[0090] The term "labeled," as used herein, refers to a compound that is associated with one or more positron-emitting radionuclides that are greater than natural abundance. For example, the labeled compounds described herein may contain one or more positron-emitting radionuclides in which atoms in the molecule (including any indicated substituents) exist as positron-emitting isotopes.

[0091] 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.

[0092] In some embodiments, the term "neurodegenerative disease" refers to a disease or condition that impairs the function of a subject's nervous system. Examples of neurodegenerative diseases include those described herein.

[0093] "Treatment" or "treating" means any treatment of a disease state in a patient; a) inhibiting the disease (e.g., reducing one or more symptoms resulting from the disease or condition and / or lessening the extent 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) To palliate the disease, i.e., to bring about a regression of clinical signs (e.g., to ameliorate the disease state, to provide partial or total relief of a disease or condition, to enhance the action of another drug, to slow the progression of a disease, to increase quality of life and / or prolong life). Includes.

[0094] "Prevention" or "preventing" means any treatment of a disease or condition that keeps the clinical signs of the disease or condition from developing. In some embodiments, the compounds 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.

[0095] "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 may 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 human.

[0096] The term "curie" (Ci) is a unit of measure of radioactivity and has its conventional meaning to those skilled in the art.

[0097] The term "diagnostic imaging," as used herein, refers to the use of electromagnetic radiation to produce pictures of internal structures of the human or animal body for diagnostic purposes.

[0098] It should be understood that certain features described herein that are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features described herein that are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. All combinations of embodiments relating to chemical groups represented by variables contained in Formula I' or Formula I or any other formula, to the extent that such combinations result in stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity), are specifically embraced herein, as if each and every combination were individually and explicitly recited. Furthermore, all subcombinations of chemical groups recited in embodiments describing such variables, and all subcombinations of uses and medical applications described herein, are also specifically embraced herein, as if each and every subcombination of chemical groups and subcombinations of uses and medical applications were individually and explicitly recited. Furthermore, some embodiments include any combination of one or more additional agents disclosed herein, as if each and every combination were individually and explicitly recited.

[0099] [Table 1] TIFF0007796054000002.tif238149TIFF0007796054000003.tif238149TIFF0007796054000004.tif50150

[0100] compound The present disclosure relates to compounds useful for imaging aggregation-prone proteins, such as huntingtin protein.

[0101] Some embodiments have Formula I':

[0102] [ka] [A 1 is C; A 2 is C or N; A 3 is CR 21 , N.R. 3 , or N; A 4 is CR 22 , N.R. 3 , or N; A 5 is 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 is CR 11 Or N and A 7 is CR 12 Or N and A 8 is CR 13 Or N and A 9 is CR 14 Or N and A 6 , A 7 , A 8 , and A 9 Not more than two of are N; R 11 , R12 , 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, C 1~4 Haloalkoxy, or -Sn(C 1~6 alkyl)3; 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, C 1~4 Haloalkoxy, Sn(C 1~6 alkyl)3, or -I + -(phenyl substituted with 1 to 3 methyl groups); X 2 is O, S, or NR 5 and 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 may be linked together with any intervening atoms to form a 3- to 6-membered ring; L 1 is 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, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein the compound is labeled with one or more radioactive isotopes.

[0103] Some embodiments have Formula I':

[0104] [ka] [A 1 is C; A 2 is C or N; A 3 is CR 21 , N.R. 3 , or N; A 4 is CR 22 , N.R. 3 , or N; A 5 is CR 23 , N.R. 3 , or N; -A 1 -A 2 -A3 -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 is CR 11 Or N and A 7 is CR 12 Or N and A 8 is CR 13 Or N and A 9 is CR 14 Or N and A 6 , A 7 , A 8 , and A 9 Not 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, C 1~4 Haloalkoxy, or -Sn(C 1~6 alkyl)3; X 1 is C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 aryl, heteroaryl, or heterocyclyl; X 1 is 1 to 4 R4 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, C 1~4 Haloalkoxy, Sn(C 1~6 alkyl)3, or -I + -(phenyl substituted with 1 to 3 methyl groups); X 2 is O, S, or NR 5 and 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 may be linked together with any intervening atoms to form a 3- to 6-membered ring; L 1 is 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 7are 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, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, optionally labeled with one or more radioactive isotopes.

[0105] In some embodiments, the compound of formula I' is labeled with a radioactive isotope.

[0106] In some embodiments, the compound is 7-bromo-5-(4-oxo-4-(pyrrolidin-1-yl)butyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one, N-(2,4-dimethoxyphenyl)-3-(4-oxopyrrolo[1,2-a]quinoxalin-5(4H)-yl)propanamide, 7-fluoro-5-[4-(morpholin-4-yl)-4-oxobutyl]-4H,5H-pyrrolo[1,2-a]quinoxalin-4-one, 5-[4-(3,5-dimethylpiperidin-1-yl)-4- oxobutyl]-4H,5H-pyrrolo[1,2-a]quinoxalin-4-one, N-(4-methylphenyl)-3-{4-oxo-4H,5H-pyrrolo[1,2-a]quinoxalin-5-yl}propanamide, 7-bromo-5-[4-oxo-4-(piperidin-1-yl)butyl]-4H,5H-pyrrolo[1,2-a]quinoxalin-4-one, or 7-fluoro-5-[2-oxo-2-(piperidin-1-yl)ethyl]-4H,5H-pyrrolo[1,2-a]quinoxalin-4-one.

[0107] Some embodiments are represented by Formula I:

[0108] [ka] [A 1 is C; A 2is C or N; A 3 is CR 21 , N.R. 3 , or N; A 4 is CR 22 , N.R. 3 , or N; A 5 is 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 is CR 11 Or N and A 7 is CR 12 Or N and A 8 is CR 13 Or N and A 9 is CR 14 Or N and A 6 , A 7 , A 8 , and A 9 Not more than two of are N; R 11 , R 12 , R 13 , and R 14Each 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 and 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 may be linked together with any intervening atoms to form a 3- to 6-membered ring; L 1 is C(O), C(O)NR a , N.R. a C(O), or O, or L 1 does not exist; R a is hydrogen, C1~6 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, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, optionally labeled with one or more radioactive isotopes.

[0109] In some embodiments, the compound of formula I is labeled with a radioisotope.

[0110] In some embodiments, the compound is 7-bromo-5-(4-oxo-4-(pyrrolidin-1-yl)butyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one, N-(2,4-dimethoxyphenyl)-3-(4-oxopyrrolo[1,2-a]quinoxalin-5(4H)-yl)propanamide, 7-fluoro-5-[4-(morpholin-4-yl)-4-oxobutyl]-4H,5H-pyrrolo[1,2-a]quinoxalin-4-one, 5-[4-(3,5-dimethylpiperidin-1-yl)-4- oxobutyl]-4H,5H-pyrrolo[1,2-a]quinoxalin-4-one, N-(4-methylphenyl)-3-{4-oxo-4H,5H-pyrrolo[1,2-a]quinoxalin-5-yl}propanamide, 7-bromo-5-[4-oxo-4-(piperidin-1-yl)butyl]-4H,5H-pyrrolo[1,2-a]quinoxalin-4-one, or 7-fluoro-5-[2-oxo-2-(piperidin-1-yl)ethyl]-4H,5H-pyrrolo[1,2-a]quinoxalin-4-one.

[0111] In some embodiments, a compound of Formula I: [In the formula, A 1 is C; A 2 is C or N; A 3 is CR 21 , N.R. 3 , or N; A 4 is CR 22 , N.R. 3 , or N; A 5 is CR 23 and; -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 is CR 11 Or N and A 7 is CR 12 Or N and A 8 is CR 13 Or N and A 9 is CR 14 Or N and A 6 , A 7 , A 8 , and A 9 At most one of is 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 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 and 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 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; L 1 is C(O), C(O)NR a or NR a C(O); R a is hydrogen, C 1~6 Alkyl or C 1~6is 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] A compound of the formula Provided is a compound that is not 7-bromo-5-(4-oxo-4-(pyrrolidin-1-yl)butyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one or N-(2,4-dimethoxyphenyl)-3-(4-oxopyrrolo[1,2-a]quinoxalin-5(4H)-yl)propanamide, or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0112] In some embodiments, a compound of Formula I:

[0113] [ka] [In the formula, A 1 is C; A 2 is C or N; A 3 is CR 21 , N.R. 3 , or N; A 4 is CR 22 , N.R. 3 , or N; A 5 is CR 23 and; -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 is CR 11 Or N and A 7 is CR 12 Or N and A 8 is CR 13 Or N and A 9 is CR 14 Or N and A 6 , A 7 , A 8 , and A 9 At most one of is 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 3~10 Cycloalkyl, C 6~10 aryl, heteroaryl, or heterocyclyl; X 1 is 1 to 4 R 4 is optionally replaced by; Each R 4are 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 and 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 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; L 1 is C(O), C(O)NR a or NR a C(O); 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] A compound of the formula Provided is a compound that is not 7-bromo-5-(4-oxo-4-(pyrrolidin-1-yl)butyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one or N-(2,4-dimethoxyphenyl)-3-(4-oxopyrrolo[1,2-a]quinoxalin-5(4H)-yl)propanamide, or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0114] In some embodiments, a compound of Formula I: [In the formula, A 1 is C; A 2 is C or N; A 3 is CR 21 , N.R. 3 , or N; A 4 is CR 22 , N.R. 3 , or N; A 5 is CR 23 and; -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 is CR11 Or N and A 7 is CR 12 Or N and A 8 is CR 13 Or N and A 9 is CR 14 Or N and A 6 , A 7 , A 8 , and A 9 At most one of is 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 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 and 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 2, 3, or 4; Each R 6 are independently hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, C 1~4Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy or C 1~4 haloalkoxy; L 1 is C(O), C(O)NR a or NR a C(O); 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] A compound of the formula 7-fluoro-5-[4-(morpholin-4-yl)-4-oxobutyl]-4H,5H-pyrrolo[1,2-a]quinoxalin-4-one, 5-[4-(3,5-dimethylpiperidin-1-yl)-4-oxobutyl]-, not 7-bromo-5-(4-oxo-4-(pyrrolidin-1-yl)butyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one or N-(2,4-dimethoxyphenyl)-3-(4-oxopyrrolo[1,2-a]quinoxalin-5(4H)-yl)propanamide Provided is a compound that is not 4H,5H-pyrrolo[1,2-a]quinoxalin-4-one, N-(4-methylphenyl)-3-{4-oxo-4H,5H-pyrrolo[1,2-a]quinoxalin-5-yl}propanamide, or 7-bromo-5-[4-oxo-4-(piperidin-1-yl)butyl]-4H,5H-pyrrolo[1,2-a]quinoxalin-4-one, or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0115] In some embodiments, the compound of formula I has formula Ia:

[0116] [ka] or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0117] In some embodiments, the compound of Formula I has Formula IIa:

[0118] [ka] [R b Ha-L 2 -X 1 and R a is as defined herein; or R a and R b is one to four R with any intervening atoms. 4 forming a 3- to 10-membered heterocyclyl ring optionally substituted by or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0119] In some embodiments, the compound of Formula I has Formula IIb:

[0120] [ka] [R b Ha-L 2 -X 1 and R a is as defined herein; or R a and R b is one to four R with any intervening atoms. 4 forming a 3- to 10-membered heterocyclyl ring optionally substituted by or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0121] In some embodiments, the compound of formula I has formula IIc:

[0122] [ka] [R b Ha-L 2 -X 1 and R a is as defined herein; or R a and R b is one to four R with any intervening atoms. 4 forming a 3- to 10-membered heterocyclyl ring optionally substituted by or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0123] In some embodiments, the compound of formula I has formula IId:

[0124] [ka] [R b Ha-L 2 -X 1 and R a is as defined herein; or R a and R b is one to four R with any intervening atoms. 4 forming a 3- to 10-membered heterocyclyl ring optionally substituted by or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0125] In some embodiments, R 11 , R12 , R 13 , or R 14 In some embodiments, one of R 11 , R 12 , R 13 , or R 14 In some embodiments, one of R 13 is halo. In some embodiments, R 13 is fluoro. In some embodiments, R 11 , R 12 , R 13 , and R 14 Each of is hydrogen.

[0126] In some embodiments, R 11 , R 12 , R 13 , and R 14 is a radioisotope, e.g. 18 Other known functional groups for the introduction of F may be used. Such functional groups include, but are not limited to, boron derivatives, NO2 derivatives, and the like.

[0127] In some embodiments, R 11 , R 12 , R 13 , or R 14 One of them is C 1~4 In some embodiments, R 11 , R 12 , R 13 , or R 14 In some embodiments, one of R 13 is methoxy.

[0128] In some embodiments, R 21 , R 22 , and R 23 In some embodiments, one of R 21 , R 22 , and R 23 In some embodiments, one of R 21 , R 22 , and R 23In some embodiments, one of R 21 , R 22 , and R 23 Each of is hydrogen.

[0129] In some embodiments, R 3 is C 1~4 In some embodiments, R 3 is methyl. In some embodiments, R 3 is hydrogen.

[0130] In some embodiments, X 1 is C 3~10 Cycloalkyl, C 6~10 In some embodiments, X is aryl, heteroaryl, or heterocyclyl. 1 is C 3~10 In some embodiments, X is cycloalkyl or heterocyclyl. 1 is C 6~10 It is aryl or heteroaryl.

[0131] In some embodiments, X 1 is C 6~10 In some embodiments, X is aryl. 1 is phenyl.

[0132] In some embodiments, X 1 is heteroaryl. In some embodiments, X 1 is pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl.

[0133] In some embodiments, X 1 is heterocyclyl. In some embodiments, X 1 is 1-piperidinyl, 4-morpholinyl, piperazin-1-yl, piperazin-3-one-1-yl, pyrrolidin-1-yl, or pyridazin-3(2H)-one-6-yl. 1 is oxo-heterocyclyl.

[0134] In some embodiments, R4 are halo, hydroxy, C 1~4 Alkyl, C 1~4 Haloalkyl, or C 1~4 In some embodiments, R 4 is halo. In some embodiments, R 4 is fluoro. In some embodiments, X 1 is phenyl and R 4 is fluoro.

[0135] In some embodiments, X 1 is phenyl and R 4 are halo, hydroxy, C 1~4 Alkyl, C 1~4 Haloalkyl, or C 1~4 It is an alkoxy.

[0136] In some embodiments, X 1 is fluorophenyl. In some embodiments, X 1 is 2-fluorophenyl. In some embodiments, X 1 is difluorophenyl. In some embodiments, X 1 is 2,4-difluorophenyl. In some embodiments, X 1 is 2,5-difluorophenyl.

[0137] In some embodiments, R a and R b is one to four R with any intervening atoms. 4 In some embodiments, R a and R b is one to four R with any intervening atoms. 4 to form 1-piperidinyl, 4-morpholinyl, piperazin-1-yl, piperazin-3-one-1-yl, pyrrolidin-1-yl, or pyridazin-3(2H)-one-6-yl optionally substituted by

[0138] In some embodiments, X 2 is O.

[0139] In some embodiments, m is 2. In some embodiments, m is 3.

[0140] In some embodiments, L 2 does not exist.

[0141] In some embodiments, each R 6 is hydrogen.

[0142] In some embodiments, A 6 is CR 11 and A 7 is CR 12 and A 8 is CR 13 and A 9 is CR 14 is.

[0143] In some embodiments, A 6 , A 7 , A 8 , and A 9 One of the is N and the rest, if applicable, are CR 11 , C.R. 12 , C.R. 13 , or CR 14 In some embodiments, A 6 is CR 11 and A 7 is CR 12 and A 8 is CR 13 and A 9 is N. In some embodiments, A 6 is CR 11 and A 7 is CR 12 and A 8 is N and A 9 is CR 14 In some embodiments, A 6 is CR 11 and A 7 is N and A 8 is CR 13 and A 9 is CR 14 is.

[0144] In some embodiments, a compound selected from the compounds of Table 1A, optionally labeled with one or more radioactive isotopes, or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof is provided. In some embodiments, a compound selected from the compounds of Table 1B, optionally labeled with one or more radioactive isotopes, or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof is provided.

[0145] In some embodiments, the compounds of formula I are labeled with one or more radioisotopes.

[0146] In some embodiments, the compound of formula I' is 11 C. 13 N, 15 O, and 18 F. In some embodiments, the compound of formula I contains one or more positron-emitting radioisotopes selected from: 11 C. 13 N, 15 O, and 18 It contains one or more positron-emitting radioisotopes selected from F.

[0147] In some embodiments, an imaging agent is provided comprising a compound of Formula I', or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof. In some embodiments, an imaging agent is provided comprising a compound of Formula I, or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0148] Also provided are additional compounds described herein. In some embodiments, a compound selected from Table 1A, or an isotopically labeled analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof is provided.

[0149] In some embodiments, a pharmaceutical composition is provided comprising a compound described herein, or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, and a pharmaceutically acceptable excipient.

[0150] Non-metallic radionuclides can be covalently bound to the compounds described herein by reactions known in the state of the art. It is understood that if the radionuclide is a metallic positron emitter, labeling may require the use of a chelating agent. Such chelating agents are well known in the state of the art.

[0151] In some embodiments, a compound is provided that is selected from the compounds described in the Examples section provided herein.

[0152] Also provided is a compound selected from Table 1A, or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof:

[0153] [Table 2] TIFF0007796054000015.tif211153TIFF0007796054000016.tif211153TIFF0007796 054000017.tif211153TIFF0007796054000018.tif211153TIFF0007796054000019.t if211153TIFF0007796054000020.tif211153TIFF0007796054000021.tif211153TIF F0007796054000022.tif211153TIFF0007796054000023.tif211153TIFF00077960540 00024.tif211153TIFF0007796054000025.tif211153TIFF0007796054000026.tif21 1153TIFF0007796054000027.tif211153TIFF0007796054000028.tif211153TIFF000 7796054000029.tif211153TIFF0007796054000030.tif211153TIFF00077960540000 31.tif211153TIFF0007796054000032.tif211153TIFF0007796054000033.tif114153

[0154] The compounds of Table 1B, or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, are as follows:

[0155] [Table 3]

[0156] Diagnostic Methods and Uses In some embodiments, provided are methods for generating diagnostic images in an individual, the method 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 body region of the individual. Generating an image of a body part or body region of the individual can include generating an image and detecting the presence or absence of an 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 diseases, and spinocerebellar ataxias.

[0157] Some embodiments provide a method of producing a diagnostic image in an individual, the method comprising administering an effective amount of a compound of formula I', or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0158] In some embodiments, a method for generating a diagnostic image in an individual comprises administering to an individual an effective amount of a compound of Formula I:

[0159] [ka] [A 1 is C; A 2 is C or N; A 3 is CR 21 , N.R. 3 , or N; A 4 is CR 22 , N.R. 3 , or N; A 5 is CR 23 , N.R. 3 , or N; -A 1 -A2 -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 is CR 11 Or N and A 7 is CR 12 Or N and A 8 is CR 13 Or N and A 9 is CR 14 Or N and A 6 , A 7 , A 8 , and A 9 Not 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 4is 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 and 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 may be linked together with any intervening atoms to form a 3- to 6-membered ring; L 1 is 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 1~4Alkoxy or C 1~4 haloalkoxy] or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, optionally labeled with one or more radioactive isotopes.

[0160] Some embodiments provide a method of producing a diagnostic image in an individual, the method comprising administering an effective amount of a compound selected from Table 1A or Table 1B, or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0161] Methods for producing diagnostic images using positron emission tomography (PET) are provided. PET imaging may be performed as known to those skilled in the art or as follows. PET imaging may involve administering a positron-emitting radionuclide tracer, such as a compound or imaging agent described herein, to an individual. The tracer is then allowed sufficient time to bind to the protein of interest, 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 individual's tissues until it interacts with an electron. This interaction annihilates both the electron and the positron, generating a pair of photons. The photons are detected by a scintillator in the scanning device. Non-paired photons are ignored.

[0162] Also provided are methods of producing diagnostic images, including PET with simultaneous computed tomography imaging (PET / CT), PET with simultaneous magnetic resonance imaging (PET / MRI), or single photon emission computed tomography (SPECT) imaging. Generally, computed tomography uses x-rays or gamma rays to detect brain structures, while magnetic resonance imaging uses magnetic fields and radio waves.

[0163] 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 aggregation-prone proteins or aggregates thereof. When the compounds or imaging agents are labeled with a radioisotope, the emitted particles can be detected.

[0164] In some embodiments, the compound or imaging agent is administered to the vasculature 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 individual's brain, e.g., a portion into which the compound is distributed.

[0165] Also provided are methods for generating a diagnostic image in a biological sample, comprising contacting the biological sample with an effective amount of a compound or imaging agent described herein and generating an image associated with the biological sample. In some embodiments, the contacting and generating may be performed in vitro. In some embodiments, the contacting is in vivo and the generating is in vitro.

[0166] Also provided are methods for detecting the presence or absence of a pathological process associated with a protein prone to protein aggregation, such as huntingtin protein (HTT protein), in an individual, the methods comprising administering an effective amount of a compound or imaging agent described herein; generating an image and detecting the presence or absence of huntingtin protein (HTT protein) in the image; and detecting the presence or absence of the pathological process, such as a neurodegenerative disease. In some embodiments, the HTT protein exists as a monomer, oligomer, or aggregate, or a combination thereof. In some embodiments, the aggregation-prone protein is huntingtin protein (HTT protein). The HTT protein can be a mutant. In some embodiments, the HTT protein is found in the brain, for example, in the basal ganglia.

[0167] In some embodiments, the body part or body region is selected from the head, spinal cord, limbs, chest, and / or abdomen. In some embodiments, the body part or body region is the brain. In some embodiments, the HTT protein is found in the basal ganglia. In some embodiments, the 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, 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.

[0168] In some embodiments, the individual has or is found to have Huntington's disease.

[0169] Also provided are methods for detecting the presence or absence of a pathological process associated with β-amyloid protein in an individual, the methods comprising administering an effective amount of a compound or imaging agent described herein; generating an image of a body part or body region of the individual; and detecting the presence or absence of the pathological process. In some embodiments, the individual has or is found to have Alzheimer's disease (AD).

[0170] 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.

[0171] In some embodiments, compounds are provided that have binding rates for protein aggregates, such as HTT protein aggregates or β-amyloid protein aggregates, suitable for functioning as imaging agents. Accordingly, the compounds described herein may be characterized by one or more of: 1) high affinity for such protein aggregates; 2) low affinity for neighboring structures; and / or 3) slow dissociation rates from such protein aggregates. The dissociation rate can be calculated by the following formula: assn is the association rate constant) diss It can be expressed as: d[AB] / dt = k assn [A][B] - k diss [AB]

[0172] 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.

[0173] 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 Br may be used. 99m Incorporation of chelated radionuclides, such as Tc, may also be useful. 18 The longer half-life of F allows imaging to be performed for a long enough time for a stronger signal to develop. 18 F 11 C. In some embodiments, the compounds or imaging agents described herein may be labeled with a positron-emitting radionuclide or a gamma-emitting radionuclide. Some examples of positron-emitting radionuclides include: 15 O. 13 N, 11 C. 18 F, 76 Br and 124 I, which have half-lives of approximately 2, 10, 20, 110 minutes, 16 hours, and 4.2 days, respectively.

[0174] In some embodiments, the compounds or imaging agents described herein are 11 C and 18 The molecule may be labeled with a positron emitter selected from F. 11 The method for introducing C is 11 C] iodomethane or [ 11 Carbon-11 has a half-life of approximately 20 minutes, and therefore 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 The radiopharmaceutical is converted to [C]iodomethane, etc., and the synthesis of the radiopharmaceutical is completed on-site for use in PET imaging studies after the appropriate radiochemical purity and specific activity have been determined. 18Exemplary methods for introducing F include, but are not limited to, nucleophilic and electrophilic methods. Nucleophilic methods include displacement of a halide, tosylate, or other leaving group with labeled cesium fluoride, potassium fluoride, tetrabutylammonium fluoride, tetramethylammonium fluoride, or potassium fluoride kryptofix-222. 18 Electrophiles 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-benziodoxol, p-fluorophenylaminosulfur trifluoride, p-nitrophenylaminosulfur trifluoride, or pentafluorophenylaminosulfur trifluoride. General methods for introducing 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).

[0175] Fluorine-18 has a half-life of about 110 minutes, so [ 18Synthesis of the [F] radiopharmaceutical does not necessarily have to be performed at a cyclotron site or near 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 relatively short 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 excellent resolution limits for PET imaging.

[0176] As will be recognized, the steps of the methods described herein need not be performed a particular number of times or in a particular order. Additional objects, advantages, and novel features of the present invention will become apparent to those skilled in the art upon examination of the following examples, which are intended to be illustrative and not limiting.

[0177] Application and Treatment Methods The compounds or imaging agents described herein may be useful for treating diseases or conditions mediated at least in part by aggregation-prone proteins. In some embodiments, the compounds or imaging agents described herein are useful for treating diseases or conditions mediated at least in part by HTT proteins. 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, provided are methods for 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.

[0178] Some embodiments provide a method for treating 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 of Formula I', or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0179] In some embodiments, there is provided a method for treating 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 protein of Formula I; [A 1 is C; A 2 is C or N; A 3 is CR 21 , N.R. 3 , or N; A 4 is CR 22 , N.R. 3 , or N; A 5 is 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 C3~6 is cycloalkyl; A 6 is CR 11 Or N and A 7 is CR 12 Or N and A 8 is CR 13 Or N and A 9 is CR 14 Or N and A 6 , A 7 , A 8 , and A 9 Not 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 and 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 R6 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 may be linked together with any intervening atoms to form a 3- to 6-membered ring; L 1 is 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, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, optionally labeled with one or more radioactive isotopes.

[0180] Some embodiments provide a method for treating 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 selected from Table 1A or Table 1B, or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof.

[0181] Exemplary diseases and conditions are listed below.

[0182] Huntington's disease (HD) Huntington's disease (HD) is a hereditary, progressive neurodegenerative disorder characterized by motor, cognitive, and psychiatric impairments, as well as neurodegeneration and brain atrophy. Atrophy begins in the striatum and cortex and spreads to other subcortical brain regions. HD belongs to a group of neurodegenerative disorders in which expanded CAG repeats result in long stretches of polyglutamine (polyQ) in the encoded protein. This group also includes dentatorubral-pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and spinocerebellar ataxias (SCAs). In HD, selective neurodegeneration of gamma-aminobutyric acid-releasing spiny-projection neurons in the striatum has been observed, but neuronal loss in many other brain regions has also been reported. Symptoms of HD include loss of motor control, psychiatric symptoms, and memory and / or cognitive impairment.

[0183] The HD protein huntingtin (HTT protein) is a 348 kDa multidomain protein containing a polymorphic glutamine / proline-rich domain at its amino terminus. 15 The number of CAG repeats in the gene varies from 6 to 35 in healthy individuals, with 36 or more repeats defining the HD allele. The length of the CAG expansion is inversely correlated with the age of disease onset, with early-onset cases characterized by expansions of more than 60 repeats. Longer polyQ domains are thought to cause conformational changes in the HTT protein, leading to the formation of intracellular aggregates that often appear as nuclear inclusions. However, aggregates can also form outside the nucleus. The HTT protein is present in the nucleus, cell body, dendrites, and nerve terminals of neurons and is also associated with many organelles, including the Golgi apparatus, endoplasmic reticulum, and mitochondria.

[0184] The part of the brain most affected by HD, and therefore most likely to contain HTT protein abnormalities, is a group of nerve cells at the base of the brain collectively known as the basal ganglia. The basal ganglia organize muscle-propelled body movements, or "motor activity." The main components of the basal ganglia are the caudate nucleus and putamen (together known as the striatum) and the globus pallidus (external and internal regions). The substantia nigra and subthalamic nucleus are often included as part of the basal ganglia as well.

[0185] The basal ganglia are a group of subcortical nuclei primarily responsible for motor control, as well as other roles such as motor learning, executive function, behavior, and emotion. Disruption of the basal ganglia network is thought to lead to several movement disorders. Normal function of the basal ganglia requires fine-tuning of neuronal excitability within each nucleus to determine the degree of motor facilitation or inhibition at any given time. This is mediated by the complex organization of the striatum, where the excitability of medium spiny neurons is controlled by several pre- and post-synaptic mechanisms and interneuron activity, and ensured by several recurrent or internal basal ganglia circuits. The basal ganglia motor circuit has two input points, the striatum and subthalamic nucleus, and one output point, the internal pallidal segment, which connects to the cortex via the motor thalamus.

[0186] 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.

[0187] Neurodegenerative diseases are diseases or conditions that impair the function of a subject's nervous system. Examples of neurodegenerative diseases include, for example, Alexander 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 disease, and Krabbe disease. , kuru, dementia with Lewy bodies, 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 degeneration secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia, spinal muscular atrophy, Steele-Richardson-Olszewski disease, insulin resistance, or tabes dorsalis.

[0188] 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.

[0189] The compounds described herein, when administered to a subject, can inhibit neuronal degeneration. In some embodiments, inhibiting neuronal degeneration can include inhibiting the degeneration of axons or neurons in neurons. Such inhibition can involve the entire neuron or a portion thereof, e.g., the neuronal cell body, axons, and dendrites. This can be assessed, for example, by analyzing nervous system function using methods known in the art. Administration of a compound described herein can 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.

[0190] 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 neuron 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.

[0191] Additionally, the compounds described herein can be used to prevent or treat memory loss. Types of memory that are affected by loss and therefore can be treated by the present disclosure include episodic memory, semantic memory, short-term memory, and long-term memory.

[0192] 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.

[0193] 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 diseases, and spinocerebellar ataxias. In some embodiments, the neurodegenerative disease is classified as a triplet repeat disease. In some embodiments, the triplet repeat disease is classified as belonging to Category I, Category II, or Category III.

[0194] In some embodiments, the neurodegenerative disease is Huntington's disease.

[0195] 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.

[0196] Imaging agents and pharmaceutical compositions Imaging agents generally include compounds described herein labeled with a positron-emitting radionuclide. Positron-emitting radionuclide-labeled imaging agents are typically administered via intravenous injection immediately (e.g., within one hour of synthesis) due to the short half-life of the radionuclide. The amount of imaging agent required is typically determined by the prescribing physician. Dosages can vary depending on various factors, including, but not limited to, the binding rate of the compound, the amount of emission from the radionuclide used, the half-life of the radionuclide, the body part, body region, and / or tissue to be imaged, and individual characteristics. Those skilled 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 amount of labeled compound in an effective amount of imaging agent may be about 0.1 to about 500 mg.

[0197] In general, the compounds or imaging agents described herein can be administered to a patient in need thereof via any suitable route. Routes of administration can include parenteral administration, such as subcutaneous, intramuscular, or intravenous, for example, via a drip patch. Further suitable routes of administration include, but are not limited to, oral, rectal, intranasal, topical (including buccal and sublingual), injection, vaginal, intradermal, intraperitoneal, intracranial, intrathecal, and epidural administration, for example, via a spray or inhaler, or via an implant, or via oral or nasal inhalation.

[0198] For PET imaging, administration of the compounds or imaging agents described herein to an individual may be intravenous. Pharmaceutical compositions may take the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents, as described herein. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable vehicles, such as solutions in 1,3-butanediol. Among the acceptable vehicles that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating, fixed oil may be used, including synthetic mono- and diglycerides. Additionally, fatty acids, such as oleic acid, may be useful in the preparation of injectables. Such solutions may be formulated as 0.01% to 10% isotonic solutions, pH 5 to 7, and appropriate salts.

[0199] The compounds or imaging agents described herein may be administered parenterally in a sterile medium. Parenteral administration includes subcutaneous injection, intravenous, intramuscular, intrathecal injection, or infusion techniques. The compounds or imaging agents described herein may be suspended or dissolved in a vehicle, depending on the vehicle and concentration used. Advantageously, adjuvants such as local anesthetics, preservatives, and buffering agents can be dissolved in the vehicle. In many pharmaceutical compositions for parenteral administration, the carrier accounts for at least 90% by weight of the total composition. In some embodiments, the carrier for parenteral administration is selected from propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil.

[0200] Pharmaceutical compositions, such as injectable pharmaceutical compositions, can include cyclodextrin. The cyclodextrin can be, for example, hydroxypropyl cyclodextrin or sulfobutyl ether cyclodextrin. The cyclodextrin can be, for example, α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin.

[0201] The compounds or imaging agents described herein may be administered via microspheres, liposomes, other microparticulate delivery systems, or sustained-release formulations placed in specific tissues, including blood. Suitable examples of sustained-release carriers include semipermeable polymer matrices in the form of co-medical products, such as suppositories or microcapsules. Examples of the above techniques or protocols and other techniques or protocols that can be used in accordance with the present invention can be found in Remington's Pharmaceutical Sciences, 18th Edition, Gennaro, AR, Lippincott Williams & Wilkins; 20th Edition (December 15, 2000) ISBN 0-912734-04-3 and Pharmaceutical Dosage Forms and Drug Delivery Systems, Ansel, NC et al., 7th Edition, ISBN 0-683305-72-7, the entire contents of which are incorporated herein by reference.

[0202] In some embodiments, the compounds or imaging agents described herein are administered as pharmaceutical compositions.Therefore, pharmaceutical compositions are provided that include at least one compound or imaging agent described herein, together with at least one pharmaceutically acceptable vehicle selected from carriers, adjuvants, and excipients.The compounds or imaging agents of the present invention can be formulated into pharmaceutical compositions using techniques known to those skilled in the art.

[0203] Pharmaceutically acceptable vehicles must be of sufficiently high purity and sufficiently low toxicity to make them suitable for administration to the animal being treated. The vehicle can be inert, or it can have a pharmaceutical benefit. The amount of vehicle used with the compound or imaging agent can be sufficient to provide a practical amount of material for administration per dose of compound or imaging agent.

[0204] Exemplary pharmaceutically acceptable carriers or components thereof are sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and methylcellulose; powdered tragacanth; malt; gelatin; talc; solid lubricating oils such as stearic acid and magnesium stearate; calcium sulfate; synthetic oils; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, and corn oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; phosphate buffer solutions; emulsifiers such as TWEEN®; wetting agents such as sodium lauryl sulfate; colorants; flavorings; tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0205] 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.

[0206] At least one compound or imaging agent described herein at an effective concentration is mixed with a suitable pharmaceutically acceptable vehicle.If the compound or imaging agent shows insufficient solubility, a method for solubilizing the compound may be used.Such methods are known to those skilled in the art and include, but are not limited to, using a cosolvent such as dimethyl sulfoxide (DMSO), using a surfactant such as TWEEN®, or dissolving in an aqueous buffer solution, such as sodium bicarbonate.

[0207] Upon mixing or addition of a compound or imaging agent described herein, the resulting mixture may be a solution, suspension, emulsion, etc. The form of the resulting mixture will depend on many factors, including the intended method of administration and the solubility of the compound or imaging agent in the selected vehicle. Effective concentrations sufficient for imaging or treatment can be determined empirically by methods known in the art.

[0208] Pharmaceutical compositions may be formulated for oral use, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Pharmaceutical compositions intended for oral use may be prepared according to any method known to those skilled in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, such as sweeteners, flavoring agents, coloring agents, and preservatives, to provide a pharmaceutically simple and palatable product. In some embodiments, oral pharmaceutical compositions contain 0.1-99% of a compound or imaging agent described herein. In some embodiments, oral pharmaceutical compositions contain at least 5% (by weight) of a compound or imaging agent. Some embodiments contain 25%-50% or 5%-75% of a compound or imaging agent.

[0209] Orally administered pharmaceutical compositions also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups, etc. Pharmaceutically acceptable carriers suitable for preparing such compositions are well known in the art. Oral pharmaceutical compositions may also contain preservatives, flavoring agents, sweeteners such as sucrose or saccharin, taste-masking agents, and coloring agents.

[0210] 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.

[0211] The compounds or imaging agents described herein can be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs. Additionally, pharmaceutical compositions containing the compounds or imaging agents described herein can be presented as a dry product for constitution with water or another suitable vehicle before use. Such liquid preparations can contain conventional additives, such as suspending agents (e.g., sorbitol syrup, methylcellulose, glucose / sugar, syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, and hydrogenated edible fats), emulsifiers (e.g., lecithin, sorbitan monooleate, or acacia), non-aqueous vehicles, such as edible oils (e.g., almond oil, fractionated coconut oil, silyl esters, propylene glycol, and ethyl alcohol), and preservatives (e.g., methyl or propyl p-hydroxybenzoates and sorbic acid).

[0212] 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.

[0213] Aqueous suspensions are provided containing the compound or imaging agent in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia. Dispersing or wetting agents can be naturally occurring phosphatides, such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitols, such as substituted polyethylene sorbitols, or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitol anhydrides, such as substituted polyethylene sorbitan. Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate.

[0214] Oily suspensions can be formulated by suspending the compound or imaging agent in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil, such as liquid paraffin. Oily suspensions can contain thickening agents, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners, such as those identified above, and flavoring agents can be added to provide a palatable oral product. These pharmaceutical compositions can be preserved by adding an antioxidant, such as ascorbic acid.

[0215] The pharmaceutical composition may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring gums, such as gum acacia or gum tragacanth, naturally occurring phosphatides, such as soybean, lecithin, and esters or partial esters derived from fatty acids and hexitols, anhydrides, such as sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, such as polyethylene sorbitan monooleate.

[0216] 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.

[0217] Tablets typically contain conventional pharmaceutically acceptable adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose; binders such as starch, gelatin, and sucrose; disintegrants such as starch, alginic acid, and croscarmellose; and lubricants such as magnesium stearate, stearic acid, and talc. Lubricants such as silicon dioxide can be used to improve the flow properties of the powder mixture. Coloring agents, such as FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, can be useful adjuvants for chewable tablets. Capsules (including time-release and sustained-release formulations) typically contain one or more solid diluents as disclosed above. The selection of carrier components is often based on secondary considerations such as taste, cost, and storage stability.

[0218] The pharmaceutical compositions may be coated by conventional methods, typically with pH or time dependent coatings, so that the compound or imaging agent is released in the gastrointestinal tract in the vicinity of the desired local application or at various times to prolong the desired effect. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, ethylcellulose, Eudragit® coatings, waxes, and shellac.

[0219] 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.

[0220] The compounds or imaging agents described herein may be administered in the form of suppositories for rectal administration of the drug. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol.

[0221] The compounds or imaging agents described herein may be formulated for local or topical application, for example, for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams and lotions, and for application to the eye. Topical pharmaceutical compositions may be in any form, including, for example, solutions, creams, ointments, gels, lotions, emulsions, cleansers, moisturizers, sprays, skin patches, etc.

[0222] Topical pharmaceutical compositions comprising at least one compound described herein or an isotopically labeled analogue thereof, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or mixture of stereoisomers, or an imaging agent described herein can be mixed with a variety of carrier materials well 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.

[0223] Other materials suitable for use in topical carriers include, for example, emollients, solvents, humectants, thickeners, and powders. Examples of each of these types of materials, which may be used alone or in mixtures with one or more other materials, are as follows:

[0224] Representative emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecane-2-ol, isocetyl alcohol, cetyl palmitate, and dimethylpolysiloxane. , di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, peanut oil, castor oil, acetylated lanolin alcohol, petroleum oil, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate and myristyl myristate; propellants such as propane, porcine solvents such as ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran; humectants such as glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, and gelatin; and powders such as chalk, talc, fuller's earth, kaolin, starch, gum, colloidal silicon dioxide, sodium polyacrylate, tetraalkylammonium smectite, trialkylarylammonium smectite, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose, and ethylene glycol monostearate.

[0225] The compounds or imaging agents described herein may also be formulated for transdermal administration as a transdermal patch.

[0226] The compounds or imaging agents described herein may also be administered in a liposome delivery system. Liposomes can be classified into small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of amphiphilic molecules, particularly phospholipids. Liposome components include cholesterol, stearylamine, and / or phosphatidylcholine. Liposomes are suitable for various routes of administration, including topical administration and injection into various tissues. Thus, intravitreal (e.g., in the treatment of glaucoma), intraperitoneal, intravenous, intravascular, intraarticular, and intramuscular administration of liposomes are contemplated.

[0227] Other pharmaceutical compositions useful for achieving systemic delivery of compounds or imaging agents include sublingual, buccal, and nasal dosage forms. Such pharmaceutical compositions typically contain soluble filler substances such as sucrose, sorbitol, and mannitol, and one or more binders such as acacia, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose. The glidants, lubricants, sweeteners, colorants, antioxidants, and flavoring agents disclosed above may also be included.

[0228] Pharmaceutical compositions for inhalation can typically be provided in the form of a solution, suspension or emulsion, which can be administered as a dry powder or in the form of an aerosol using conventional propellants (e.g., dichlorodifluoromethane or trichlorofluoromethane).

[0229] The pharmaceutical compositions may optionally include an activity enhancer. Activity enhancers can be selected from a wide variety of molecules that function in a variety of ways that enhance or are independent of the therapeutic effect of the compounds or imaging agents described herein. Particular classes of activity enhancers include skin penetration enhancers and absorption enhancers.

[0230] The pharmaceutical compositions may contain additional active agents, which may be selected from a wide variety of molecules that function in various ways to enhance the therapeutic effect of the compounds or imaging agents described herein. When present, these optional other active agents are typically utilized in the pharmaceutical composition at levels ranging from 0.01% to 15%. In some embodiments, they comprise 0.1% to 10% by weight of the composition. In other embodiments, they comprise 0.5% to 5% by weight of the composition.

[0231] The dosage of the compounds or imaging agents described herein will depend on a variety of factors, including the particular pathological process being treated or detected, the physiology of the individual, the severity of the symptoms, the route of administration, the frequency of dosing intervals, the particular compound utilized, the efficacy of the compound, the toxicological profile, the pharmacokinetic profile, and the presence of toxic side effects, and other considerations. The dosage for a particular situation will be determined appropriately by the practitioner based on these and other factors.

[0232] The compounds or imaging agents described herein are typically administered at dosage levels determined by a practitioner, such as a physician. For example, the compounds or imaging agents are generally administered at dosage levels of 0.001-100 mg / kg, e.g., 0.01-100 mg / kg, e.g., 0.1-70 mg / kg, e.g., 0.5-10 mg / kg, in single or multiple doses. Dosages may be, for example, once daily or twice daily. A unit dosage form may generally contain 0.01-1000 mg, e.g., 0.1-50 mg, of a compound or imaging agent described herein. For intravenous administration, the compounds or imaging agents may be administered at dosage levels of, for example, 0.001-50 mg / kg, e.g., 0.001-10 mg / kg, e.g., 0.01-1 mg / kg, in single or multiple doses. A unit dosage form may contain, for example, 0.1 to 10 mg of compound or imaging agent.

[0233] Kits and Packaging Also provided herein are kits comprising a compound or imaging agent 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 using the compound in the treatment of an indication, including a disease or condition described herein.

[0234] Also provided herein are articles 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.

[0235] Packaged pharmaceutical compositions are also provided. Such packaged compositions include a pharmaceutical composition containing a compound or imaging agent described herein and instructions for using the composition to treat a subject (typically a human patient). In some embodiments, the instructions are for using the pharmaceutical composition to detect a disease or condition described herein. The packaged pharmaceutical composition may include prescribing information, for example, to the patient or healthcare provider, or as a label on the packaged pharmaceutical composition. The prescribing information may include, for example, efficacy, dosage and administration, contraindications, and adverse reaction information for the pharmaceutical composition.

[0236] In all of the foregoing, the compounds or imaging agents may be administered alone, as mixtures, or in combination with other active agents.

[0237] 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 can be Huntington's disease.

[0238] 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 can be Huntington's disease.

[0239] 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 present 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.

[0240] Pharmaceutical compositions are also provided that include 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.

[0241] Also provided are methods for treating or preventing Alzheimer's disease, including memory and / or cognitive impairment associated with Alzheimer's disease, comprising administering to a subject, simultaneously or sequentially, a compound or imaging agent described herein and one or more additional agents. In some embodiments, the active agent is Reminyl® (galantamine), Cognex® (tacrine), Aricept® (donepezil), Exelon® (rivastigmine), Akatinol® (memantine), Neotropin™ (somatropin), Eldepryl® (selegiline), estrogen, or clioquinol.

[0242] In some embodiments, the compounds described herein can be administered in conjunction with an active agent for treating Parkinson's disease, such as 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 in conjunction with an active agent for treating Alzheimer's disease, such as an acetylcholinesterase inhibitor (e.g., donepezil, galantamine, and rivastigmine) and / or an NMDA receptor antagonist (e.g., memantine).

[0243] Compound synthesis The compounds or imaging agents described herein can be prepared using the methods disclosed herein and routine variations thereof that are apparent from the disclosures herein and methods well known in the art. Conventional and well-known synthetic methods can be used in addition to the teachings herein. Synthesis of exemplary compounds described herein can be achieved as described in the following examples. Where available, reagents can be purchased commercially, for example, from Sigma Aldrich or other chemical suppliers.

[0244] The compounds or imaging agents described herein can be prepared from readily available starting materials, for example, 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.

[0245] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in Wuts, PGM, Greene, TW, & Greene, TW (2006), Greene's protective groups in organic synthesis. Hoboken, NJ, Wiley-Interscience and the references cited therein.

[0246] Additionally, the compounds or imaging agents described herein may contain one or more asymmetric ("chiral") centers. Thus, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are within the scope of the present invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, supercritical fluid chromatography, chiral resolving agents, and the like. When enantiomerically pure or enriched compounds are desired, chiral chromatography and / or enantiomerically pure or enriched starting materials can be utilized as conventionally used in the art or as described in the Examples.

[0247] 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 reference works such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplement (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).

[0248] 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). Generally, the term inert, as used herein with respect to a solvent, refers to a material in which a reaction is carried out that will not form the target compound of interest, even if it is a reaction that forms a carbon-carbon bond. 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.

[0249] The term "qs" means adding a quantity sufficient to achieve a stated function, for example, to bring a solution to the desired volume (ie, 100%).

[0250] It is also understood that the addition of any substituent 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.

[0251] Incorporation of labels into the compounds or imaging agents described herein may be accomplished by reacting a suitable starting material with a reagent containing a radioisotope. The methods generally follow the same principles as standard organic chemistry reactions and can be accomplished by any method known to those skilled in the art, including those provided in this disclosure.

[0252] Scheme 1 provides an exemplary synthetic route for the synthesis of compounds provided herein (e.g., compounds of Formula I' or Formula I). ​​Compounds of Formula I' or Formula I, or other formulas, or compounds disclosed herein, are generally prepared by first preparing the core from Formulas Va and Vb, and then attaching the desired substituents using appropriate conditions (e.g., nucleophilic addition, amide bond formation, or cross-coupling).

[0253] In some embodiments, the synthesis of the compounds described herein proceeds according to Scheme 1.

[0254] [ka] In Scheme 1, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , A 9 , rings Z and X 2 is as defined herein; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 51is defined as follows:

[0255] In Scheme 1, compound Vf is converted to a compound of formula I' or formula I in one or more steps.

[0256] Compound Vf can be synthesized from compound Ve in one or more steps. 5 Ha-LL 1 -L 2 -X 1 or a derivative thereof, such as a protected derivative or isotopically enriched analogue thereof, or Z 5 is LN(PG)2, L-NH(PG), L-NH2 or LC(O)Z 6 (wherein PG is a suitable amine protecting group (e.g., benzyl, tert-butoxycarbonyl, or benzyloxycarbonyl, or two PGs form a phthalimide). For example, Z 5 In X 1 The hydroxyl group on the above may be protected with a typical hydroxyl protecting group (e.g., benzyl). In compound Ve, Z 51 is Z 5 Or H. Z 5 is L-NH2 or LC(O)Z 6 If L 1 -L 2 -X 1 Z may be attached via an amide bond forming reaction (e.g., a coupling agent such as HATU, CDI, or T3P and a base such as triethylamine, diisopropylethylamine, or piperidine, or other conditions known in the art). 5 When Z is LN(PG) or L-NH(PG), amine deprotection can be carried out under standard conditions. 51 If is H, -LL 1 -L 2 -X 1 can be obtained, for example, by nucleophilic substitution reactions (e.g., by reacting a base, e.g., K2CO3, NaH, or NaOH, with a suitable electrophile Z 5 -Z 6 (In the formula, Z 6is an electrophile, for example an alkyl halide, for example an alkyl chloride or alkyl bromide, or a pseudohalide, for example a p-toluenesulfonate, or alternatively Z 5 -Z 6 may be added by conjugate addition using an α,β-unsaturated carbonyl, such as an alkyl prop-2-enoate, for example, ethyl prop-2-enoate. 5 -Z 6 If contains an ester, hydrolysis can be carried out under conditions described herein or known in the art (e.g., LiOH, NaOH, or KOH in a solvent containing water, such as methanol or THF).

[0257] Compound Ve can be synthesized from compound Vc or compound Vd by one or more steps described herein or known in the art, and compound Vc or compound Vd can be synthesized from compound Va and compound Vb, as appropriate.

[0258] Z 3 and Z 4 is a group suitable for forming an aryl-aryl bond. For example, Z 3 may be a leaving group, e.g., fluoro or a pseudohalide, e.g., sulfonyl (e.g., mesyl), and synthesis can be carried out, for example, by 3 and Z 4 The reaction proceeds by nucleophilic addition or aryl coupling reaction between Z and 4 may be a hydrogen atom, and the nucleophilic aromatic substitution is 21 by adding a nucleophilic center to the compound and providing a suitable leaving group Z 3 The reaction proceeds by displacing the aryl group (e.g., fluoride or nitro) and the reaction conditions include a suitable inert solvent (e.g., a polar aprotic solvent, such as DMF or acetonitrile) and elevated temperature (e.g., 50-200°C), optionally in the presence of a base (e.g., NaH or CsCO).

[0259] Z 1 and Z 2is a suitable group for the formation of a cyclic amide.

[0260] For example, Z 1 is an amine or amide (e.g., —C(O)NH(PG), —C(O)N(PG) or —C(O)NH-Z 51 In such embodiments, Z 1 may contain a nitrogen-containing functional group such as nitro, amine, or protected amine (where the protecting group is, for example, benzyl, carbamate, e.g., benzyl tert-butoxycarbonyl or benzyloxycarbonyl, or phthalimide); Z 1 When Z is nitro, reduction can be carried out (e.g., in situ) to form the amine. 1 In embodiments where Z is an amine, 2 may contain a carbonyl (e.g., as an ester, e.g., a methyl or ethyl ester, or a carboxylic acid), and Z 1 Z in 2 Bond formation to can be carried out by conditions for amide bond formation described herein or known in the art.

[0261] Alternatively, Z 1 may be a leaving group, e.g., fluoro or nitro, to allow nucleophilic addition or aryl coupling reactions to proceed to Z 1 and Z 2 Therefore, Z 2 When contains a nucleophilic center (e.g., Z 2 is -C(O)NH(PG), Z 2 For example, Z 2 At the amide nitrogen atom of 1 may undergo nucleophilic substitution.

[0262] In some embodiments, Z 1 is nitro. Z 1 If is nitro, Z 1 may be reduced under appropriate conditions, for example, using sodium dithionite, iron metal and an acid (e.g., acetic acid), or trichlorosilane.1 Nitro reduction and Z 1 Z in 2 The bond formation to Z can be carried out in a one-pot reaction. 1 If is nitro, Z 1 can act as a leaving group in a nucleophilic substitution. 1 is a nitro group, and the synthesis proceeds via compound Vd by exposing compound Vd to reduction and cyclization conditions involving a reducing agent (e.g., sodium dithionite, iron metal, or trichlorosilane) in a solvent (e.g., ethanol and water, acetic acid, or DCM) at a temperature between 0 and 150°C.

[0263] In some embodiments, Z 1 Z in 2 Reaction to and Z 3 Z in 4 The reaction to can occur in a single pot, in which case there is no need to isolate either Compound Vc or Compound Vd.

[0264] Those skilled in the art will appreciate that any of compounds Va, Vb, Vc, Vd, Ve, or Vf may be available from commercial sources for certain embodiments. Alternative syntheses of compounds Va, Vb, Vc, Vd, Ve, or Vf may be as described herein or known to those skilled in the art. [Example]

[0265] The following examples are included to demonstrate specific embodiments of the invention. It should be understood by those skilled in the art that the techniques disclosed in the examples which follow represent fully functional techniques in the practice of the invention and can thereby be considered to constitute specific modes for its implementation. However, in light of the present invention, those skilled in the art should appreciate that numerous changes can be made to the specific embodiments disclosed and still achieve similar results without departing from the spirit and scope of the invention.

[0266] 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, a Bruker DPX 250 MHz spectrometer, a Bruker AVANCE 300 spectrometer, or a Bruker AVANCE 500 spectrometer. 1 H NMR spectra were recorded. Chemical shifts (δ) are expressed in parts per million. Flash column chromatography refers to automated purification on a Biotage Isolera system using appropriately sized SNAP or KPNH pre-packed silica columns and solvents as recorded in the experimental section. Thin-layer chromatography (TLC) analysis was performed on Kieselgel 60 F254 (Merck) plates and visualized using UV light. SCX chromatography was performed using a Biotage Isolute FlashSCX-2, loading the sample in methanol and eluting with methanol followed by 5% ammonia in methanol.

[0267] 2.Analysis method Acid phase HPLC method Analytical HPLC-MS (METCR1673) was performed on a Shimadzu LCMS-2010EV system using a Supelco Ascentis Express reverse-phase column (2.7 μm, 2.1 × 30 mm) with a gradient of 5 to 100% B (A = water / 0.1% formic acid, B = acetonitrile / 0.1% formic acid) at a column temperature of 40 °C for 1.5 min, followed by 100% B for 0.1 min, with an injection volume of 3 μL and a flow rate of 1.0 mL / min. UV spectra were recorded at 215 nm using an SPD-M20A photodiode array (PDA) detector. Mass spectra were acquired over the m / z range of 100 to 1000 using the LCMS2010EV at a sampling rate of two scans per second. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[0268] Alternatively, HPLC-MS (METCR1410) was performed on a Shimadzu LCMS-2010EV system using a Kinetix Core-Shell C18 reverse-phase column (5 μm, 2.1 × 50 mm) with a gradient of 5 to 100% B (A = water / 0.1% formic acid, B = acetonitrile / 0.1% formic acid) for 1.2 min, followed by 100% B for 0.1 min, at a column temperature of 40 °C, with an injection volume of 3 μL and a flow rate of 1.2 mL / min. All other aspects of the method remained unchanged.

[0269] Alternatively, analytical HPLC-MS (METCR1416) was performed on a Shimadzu LCMS-2010EV system using a Waters Atlantis dC18 reverse-phase column (3 μm, 2.1 × 100 mm) with a gradient of 5–100% B (A = water / 0.1% formic acid, B = acetonitrile / 0.1% formic acid) at a column temperature of 40 °C for 5.0 min, followed by 100% B for 0.4 min, with an injection volume of 3 μL and a flow rate of 0.6 mL / min. UV spectra were recorded at 215 nm using an SPD-M20A PDA detector. Mass spectra were acquired over the m / z range of 100–1000 using the LCMS2010EV at a sampling rate of two scans per second. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[0270] 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) with a gradient of 5 to 100% B (A = water / 0.1% formic acid, B = acetonitrile / 0.1% formic acid) at a column temperature of 40 °C for 5.3 min, followed by 100% B for 0.5 min at a flow rate of 0.6 mL / min. UV spectra were recorded at 215 nm using a Waters Acquity PDA detector. Mass spectra were acquired over the m / z range of 150 to 850 using a Waters ZQ detector, with a sampling rate of 2 scans per second. OpenLynx software was used to integrate and generate reports.

[0271] Alternatively, mass spectra and LCMS analyses were obtained using a Waters Acquity SQD (ESI, UP-LCMS) (MET-AMRI001). HPLC analyses were obtained on an XBridge C18 column, 3.5 μm (4.6 × 150 mm), eluted according to solvent gradient method 1. Detection was by UV at 254 and 215 nm.

[0272] [Table 4]

[0273] Alternatively, analytical UHPLC-MS (METCR1704) was performed using a Waters UPLC™ BEH™ C18 column (2.1 mm x 50 mm, 1.7 μm; temperature: 40 °C) with an injection volume of 1 μL, a flow rate of 0.9 mL / min, and a gradient of 5 to 100% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) for 1.1 min, followed by 100% B for 0.25 min in a reversed-phase system. A second gradient of 100 to 5% B was then applied for 0.05 min and held for 0.1 min. UV spectra were recorded at 215 nm in the spectral range of 200 to 400 nm. Mass spectra were obtained using a Waters SQD or QDA detector; electrospray positive or negative ionization mode. Data integration and reporting were performed using Waters MassLynx and OpenLynx software.

[0274] Alternatively, analytical (METCR1503) HPLC-MS was performed in reverse phase using a Phenomenex Kinetex Core Shell C8 column (2.1 mm x 50 mm, 2.6 μm; temperature: 40 °C) with an injection volume of 3 μL, a flow rate of 0.6 mL / min, and a gradient of 5 to 100% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) for 4.4 min, followed by 100% B for 1.0 min. A second gradient of 100 to 5% B was then applied for 0.2 min and held for 0.58 min. UV spectra were recorded at 215 nm, with a spectral range of 210–400 nm. Mass spectra were obtained using a 2010EV detector; electrospray positive or negative ionization mode. Data integration and reporting were performed using Shimadzu LCMS-Solutions and PsiPort software.

[0275] Alternatively, analytical (MET-CR-AB106) UHPLC-MS was performed using a Waters UPLC™ CORTECS™ C8 column (2.1 mm x 100 mm, 1.6 μm; temperature: 40 °C) with a 1 μL injection volume, a flow rate of 0.6 mL / min, and a gradient of 5 to 100% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) for 5.3 min, followed by 100% B for 0.5 min. A second gradient of 100 to 5% B was then applied for 0.02 min and held for 1.18 min. For reporting purposes, UV spectra were recorded at 215 nm in the spectral range of 200–400 nm, and ELS data were collected using a Waters ACQUITY™ ELS detector. Mass spectra were obtained using a Waters SQD or Waters ACQUITY™ QDa; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0276] Alternatively, analytical (METCR1906) UHPLC-MS was performed using a Waters UPLC™ CORTECS™ C8 column (2.1 mm x 50 mm, 1.6 μm; temperature: 40 °C) with a 1 μL injection volume, a flow rate of 0.9 mL / min, and a gradient of 5 to 100% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) for 1.1 min, followed by 100% B for 0.3 min in reversed phase. A second gradient of 100 to 5% B was then applied for 0.02 min and held for 0.28 min. For reporting purposes, UV spectra were recorded at 215 nm in the spectral range of 200–400 nm using a Waters ACQUITY™ ELS detector, and Waters ELS data were collected. Mass spectra were obtained using a Waters SQD or Waters ACQUITY™ QDa; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0277] Basic Phase HPLC Method Analytical HPLC-MS (METCR0990) was performed on a Hewlett Packard HPLC system using a Phenomenex Gemini C18 reverse-phase column (3 μm, 2.0 × 50 mm) at a column temperature of 60 °C with a gradient of 1 to 100% B (A = 2 mM ammonium bicarbonate in water buffered to pH 10, B = acetonitrile) for 1.8 min, followed by 100% B for 0.3 min, with an injection volume of 3 μL and a flow rate of 1 mL / min. UV spectra were recorded at 215 nm using a Waters PDA detector. Mass spectra were acquired over the m / z range of 150 to 850 using a Waters ZQ at a sampling rate of 2 scans per second. OpenLynx software was used to integrate and generate reports.

[0278] Analytical HPLC-MS (METCR1600) was performed on a Hewlett Packard HPLC system using a Phenomenex Gemini C18 reverse-phase column (3 μm, 2.0 × 100 mm) with a gradient of 5 to 100% B (A = 2 mM ammonium bicarbonate in water buffered to pH 10, B = acetonitrile) for 5.5 min, followed by 100% B for 0.4 min, with an injection volume of 3 μL and a flow rate of 0.5 mL / min. UV spectra were recorded at 215 nm using a Waters PDA detector. Mass spectra were acquired over the m / z range of 150 to 850 using a Waters ZQ at a sampling rate of 2 scans per second. OpenLynx software was used to integrate and generate reports.

[0279] The METCR1600 method was then replaced with METCR1603 and the flow rate was increased to 0.6 mL / min, all other parameters remaining unchanged.

[0280] Alternatively, analytical HPLC-MS (MET-uHPLC-AB-102) was performed on a Waters Acquity UPLC system equipped with a Waters PDA and ELS detector, using a Waters UPLC® CSH™ column (1.7 μm, 2.1 × 100 mm) at a column temperature of 40 °C, with a gradient of 5 to 100% B (A = 2 mM ammonium bicarbonate in water buffered to pH 10, B = acetonitrile) for 5.3 min, followed by 100% B for 0.5 min, with an injection volume of 1 μL and a flow rate of 0.6 mL / min. UV spectra were recorded at 215 nm using a Waters Acquity PDA detector. Mass spectra were acquired over the m / z range of 150 to 850 using a Waters Quattro Premier XE detector, with a sampling rate of 2 scans per second. OpenLynx software was used to integrate data and generate reports.

[0281] All example compounds exhibit LC purity >95% unless otherwise stated.

[0282] Method 1 Method 1 scheme

[0283] [ka]

[0284] [Example 1-1] Step 1: 5-{4-[(2R,6R)-2,6-dimethylmorpholin-4-yl]-4-oxobutyl}-7-fluoro-4H,5H-pyrrolo[1,2-a]quinoxalin-4-one 4-(7-Fluoro-4-oxo-pyrrolo[1,2-a]quinoxalin-5-yl)butanoic acid (50 mg, 0.17 mmol) was dissolved in DMF (5 mL). HATU (100 mg, 0.26 mmol) and DIPEA (0.1 mL, 0.52 mmol) were added, followed by (2R,6R)-2,6-dimethylmorpholine (20 μL, 0.17 mmol). The reaction mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated to dryness, and the residue was partitioned between DCM (5 mL) and water (5 mL) and extracted with DCM (2 × 3 mL). The combined organics were dried (MgSO4) and concentrated. Further purification by basic preparative HPLC afforded the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 8.54 - 7.99 (m, 2H), 7.76 (d, J = 11.3 Hz, 1H), 7.39 - 7.09 (m, 1H), 7.08 - 6.98 (m, 1H), 6.80 - 6.45 (m, 1H), 4.39 - 4.03 (m, 2H), 3.96 - 3.71 (m, 2H), 3.54 (m, 2H), 3.16 (m, 2H), 2.50 - 2.42 (m, 2H), 1.94 - 1.64 (m, 2H), 1.09 (m, 6.4Hz, 6H). 19 F NMR (235 MHz, DMSO-d6) -115.02. Tr(METCR1603) = 3.85 min, (ES + ) (M+H) + 386.3, 100%.

[0285] The following was also prepared by this route:

[0286] [Table 5] TIFF0007796054000040.tif227150TIFF0007796054000041.tif239150TIFF0007796054000042.tif240150TIFF0007796054000043.tif239150 TIFF0007796054000044.tif239149TIFF0007796054000045.tif233150TIFF0007796054000046.tif220149TIFF0007796054000047.tif219150 TIFF0007796054000048.tif239151TIFF0007796054000049.tif239150TIFF0007796054000050.tif239150TIFF0007796054000051.tif239150 TIFF0007796054000052.tif239150TIFF0007796054000053.tif239150TIFF0007796054000054.tif239150TIFF0007796054000055.tif111151

[0287] Method 2 Method 2 scheme

[0288] [ka]

[0289] [Example 2-1] Step 1: Methyl 1-(3-nitro-4-pyridyl)pyrrole-2-carboxylate NaH (60%, 1.24 g, 31.0 mmol) and methyl 1H-pyrrole-2-carboxylate (3.17 g, 25.3 mmol) were dissolved in DMF (10 mL), and 4-fluoro-3-nitro-pyridine (4.00 g, 28.2 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The residue was triturated with water (50 mL) to give the title compound. 1H NMR (500 MHz DMSO-d6) δ 9.34 (s, 1H), 9.02 (d,J = 5.2 Hz, 1H), 7.76 (d,J = 5.2 Hz, 1H), 7.41 (dd,J = 2.8, 1.7 Hz, 1H), 7.14 (dd,J = 3.9, 1.7 Hz, 1H), 6.48 (dd,J = 3.9, 2.8 Hz, 1H), 3.62 (s, 3H). + ) (M+H) + 247.9, 95%.

[0290] Step 2: 2,8,11-triazatricyclo[7.4.0.0 2,6 ]Trideca-1(9),3,5,10,12-pentaen-7-one Ethanol (30 mL) and water (30 mL) were added to a mixture of methyl 1-(3-nitro-4-pyridyl)pyrrole-2-carboxylate (700 mg, 2.83 mmol) and sodium dithionite (1.97 g, 11.3 mmol). The mixture was heated at 75° C. for 8 hours. Additional sodium dithionite (1.97 g, 11.3 mmol) was added, and the reaction was stirred at room temperature overnight. The mixture was concentrated in vacuo to approximately 30 mL, diluted with water (10 mL), and filtered. The solid was dried under vacuum overnight to provide the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.54 (s, 1H), 8.35 (d,J = 5.5 Hz, 1H), 8.31 - 8.22 (m, 1H), 8.04 (d,J = 5.5 Hz, 1H), 7.18 - 6.99 (m, 1H), 6.78 (dd,J = 3.8, 2.9 Hz, 1H).

[0291] Step 3: Methyl 4-(7-oxo-2,8,11-triazatricyclo[7.4.0.0] 2,6 ]trideca-1(9),3,5,10,12-pentaen-8-yl)butanoate NaH (60%, 131 mg, 3.27 mmol) was dissolved in 2,8,11-triazatricyclo[7.4.0.0 2,6 ] was added portionwise over 5 minutes to a cold (0 °C) solution of tridec-1(9),3,5,10,12-pentaen-7-one (550 mg, 2.97 mmol). The reaction mixture was stirred at 0 °C for 10 minutes, and methyl 4-bromobutanoate (97%, 1.11 g, 5.94 mmol) was added dropwise over 5 minutes. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 7 hours. The reaction mixture was concentrated to dryness and triturated with water (50 mL). Purification by column chromatography (silica, 10-60% EtOAc in heptane) gave the title compound. 1 H NMR (500 MHz DMSO-d6) δ 8.89 (s, 1H), 8.44 (d,J = 5.4 Hz, 1H), 8.29 (dd,J = 2.9, 1.4 Hz, 1H), 8.11 (d,J = 5.4 Hz, 1H), 7.14 (dd,J = 3.8, Tr(METCR1410) = 0.80 minutes, (ES + ) (M+H) + 286, 100%.

[0292] Step 4: 4-(7-oxo-2,8,11-triazatricyclo[7.4.0.0] 2,6 ]Trideca-1(9),3,5,10,12-pentaen-8-yl)butanoic acid Methyl 4-(7-oxo-2,8,11-triazatricyclo[7.4.0.0 2,6]trideca-1(9),3,5,10,12-pentaen-8-yl)butanoate (210 mg, 0.736 mmol) was dissolved in 2 M sodium hydroxide (3.7 mL, 7.36 mmol) and stirred at room temperature for 2 hours. The reaction mixture was acidified to pH 1 with 2 M aqueous HCl, and the resulting precipitate was filtered. Trituration with methanol (2 mL) gave the title compound. 1 H NMR (500 MHz DMSO-d6) δ 9.06 (s, 1H), 8.67 (d,J = 6.1 Hz, 1H), 8.53 - 8.00 (m, 2H), 7.26 (dd,J = 3.8, 1.3 Hz, 1H), 6.91 (dd,J = 3.7, Tr(METCR1410) = 0.74 min, (ES + ) (M+H) + 272, 92%.

[0293] Step 5: 4-(7-oxo-2,8,11-triazatricyclo[7.4.0.0] 2,6 ]trideca-1(9),3,5,10,12-pentaen-8-yl)-N-(p-tolyl)butanamide p-Methylaniline (1.7 mg, 0.111 mmol) was dissolved in HATU (63 mg, 0.166 mmol), 4-(7-oxo-2,8,11-triazatricyclo[7.4.0.0 2,6 The resulting mixture was treated with a solution of 1(9),3,5,10,12-pentaen-8-yl)trideca-1(9),3,5,10,12-pentaen-8-yl)butanoic acid (30 mg, 0.111 mmol) and DIPEA (0.058 mL, 0.332 mmol) in DMF (1 mL). The reaction mixture was allowed to stand at room temperature for 1 hour. Purification by basic preparative HPLC gave the title compound. 1H NMR (500 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.94 (s, 1H), 8.45 (d, J = 5.4 Hz, 1H), 8.29 (dd, J = 2.9, 1.4 Hz, 1H), 8.11 (d, J = 5.5 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.13 (dd, J = 3.8, 1.4 Hz, 1H), 7.08 (d, J = 8.3 Hz, 2H), 6.78 (dd, J = 3.7, 2.9 Hz, 1H), 4.80 - 4.10 (m, 2H), 2.46 (t, J = 7.3 Hz, 2H), 2.23 (s, 3H), 2.03 - 1.75 (m, 2H). Tr(METCR1603) = 3.59 min m / z (ES + ) (M+H) + 361.2, 100%.

[0294] The following was also prepared by this route:

[0295] [Table 6] TIFF0007796054000058.tif84149

[0296] Method 3 Method 3 scheme

[0297] [ka]

[0298] [Example 3-1] Step 1: Methyl 1-(4-fluoro-2-nitro-phenyl)pyrrole-2-carboxylate Methyl 1H-pyrrole-2-carboxylate (5.00 g, 40.0 mmol) and CsCO (14.47 g, 44.4 mmol) were dissolved in DMF (10 mL) and 1,4-difluoro-2-nitro-benzene (7.06 g, 44.4 mmol) was added. The reaction mixture was heated to 60 °C overnight. CsCO (2.05 g, 6.29 mmol) was added and the reaction mixture was heated to 60 °C for 2 h. The reaction mixture was concentrated. The residue was partitioned between water (100 mL) and EtOAc (100 mL) and extracted with EtOAc (2 × 50 mL). The combined organics were dried (MgSO) and concentrated in vacuo. Trituration with MeCN (20 mL) gave the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 8.16 (dd, J = 8.3, 2.9 Hz, 1H), 7.86 - 7.60 (m, 2H), 7.29 (dd, J = 2.7, 1.8 Hz, 1H), 7.06 (dd, J = 3.9, 1.8 Hz, 1H), 6.39 (dd, J = 3.9, 2.7 Hz, 1H), 3.60 (s, 3H). Tr(METCR1410) = 1.16 min, (ES + ) (M+H) + 265.0, 100%.

[0299] Step 2: 7-Fluoro-5H-pyrrolo[1,2-a]quinoxalin-4-one Methyl 1-(4-fluoro-2-nitro-phenyl)pyrrole-2-carboxylate (1.00 g, 3.78 mmol) was dissolved in acetic acid (10 mL), and then iron (845 mg, 15.1 mmol) was added. The mixture was heated to 100° C. for 30 minutes. The mixture was concentrated in vacuo, and then the residue was stirred in methanol (100 ml) at 80° C. for 30 minutes. The slurry was filtered through Celite, washing with a further portion of hot methanol (100 mL). The combined filtrate was concentrated in vacuo to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ 12.69 - 10.56 (m, 1H), 8.90 - 7.71 (m, 2H), 7.62 - 6.85 (m, 3H), 6.82 - 6.45 (m, 1H).

[0300] Step 3: 3-(7-fluoro-4-oxo-pyrrolo[1,2-a]quinoxalin-5-yl)propanoic acid 7-Fluoro-5H-pyrrolo[1,2-a]quinoxalin-4-one (700 mg, 3.46 mmol) was suspended in THF (40 mL), followed by the addition of ethyl prop-2-enoate (1.8 mL, 17.3 mmol) and sodium hydroxide (692 mg, 17.3 mmol). The mixture was stirred at room temperature for 4 days. 2N HCl (25 mL) was slowly added to acidify the mixture, and the cloudy white mixture was then extracted with DCM (3 × 100 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude material was triturated with methanol (5 mL) and dried on a filter to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 12.39 (s, 1H), 8.32 - 8.06 (m, 2H), 7.52 (dd, J = 11.2, 2.5 Hz, 1H), 7.17 (td, J = 8.8, 2.5 Hz, 1H), 7.05 (dd, J = 3.8, 1.3 Hz, 1H), 6.82 - 6.60 (m, 1H), 4.57 - 4.29 (m, 2H), 2.74 - 2.54 (m, 2H).

[0301] Step 4: 7-Fluoro-5-[3-oxo-3-(piperidin-1-yl)propyl]-4H,5H-pyrrolo[1,2-a]quinoxalin-4-one 3-(7-Fluoro-4-oxo-pyrrolo[1,2-a]quinoxalin-5-yl)propanoic acid (80 mg, 0.3 mmol) was dissolved in DMF (2 mL), followed by the addition of piperidine (89 μL, 0.9 mmol), followed by the addition of HATU (172 mg, 0.45 mmol). The mixture was stirred at room temperature for 15 minutes. The reaction mixture was purified by basic preparative HPLC to give the title compound. 1 H NMR (500 MHz, chloroform-d) δ 7.64 (dd, J = 9.0, 5.2 Hz, 1H), 7.59 (dd, J = 2.7, 1.5 Hz, 1H), 7.23 (dd, J = 10.6, 2.6 Hz, 1H), 7.21 (dd, J = 3.9, 1.5 Hz, 1H), 6.95 (ddd, J = 9.0, 7.5, 2.6 Hz, 1H), 6.66 (dd, J = 3.9, 2.8 Hz, 1H), 4.60 - 4.36 (m, 2H), 3.64 - 3.51 (m, 2H), 3.45 - 3.35 (m, 2H), 2.96 - 2.53 (m, 2H), 1.69 - 1.59 (m, 2H), 1.59 - 1.50 (m, 4H). 19 F NMR (235 MHz, chloroform-d) δ -114.07. Tr(MET-uHPLC-AB-101) = 2.97 min, (ES + ) (M+H) + 342.3, 99%.

[0302] The following was also prepared by this route:

[0303] [Table 7] TIFF0007796054000061.tif232149TIFF0007796054000062.tif232150TIFF0007796054000063.tif23 9151TIFF0007796054000064.tif239150TIFF0007796054000065.tif240151TIFF0007796054000066.t if227151TIFF0007796054000067.tif239151TIFF0007796054000068.tif228150TIFF00077960540000 69.tif240150TIFF0007796054000070.tif240150TIFF0007796054000071.tif240150TIFF00077960540 00072.tif240150TIFF0007796054000073.tif240150TIFF0007796054000074.tif240150TIFF0007796 054000075.tif222150TIFF0007796054000076.tif222150TIFF0007796054000077.tif222150TIFF000 7796054000078.tif234150TIFF0007796054000079.tif234150TIFF0007796054000080.tif234150TIF F0007796054000081.tif242150TIFF0007796054000082.tif241151TIFF0007796054000083.tif126151

[0304] Method 4 Method 4 scheme

[0305] [ka]

[0306] [Example 4-1] Step 1: Follow the steps in Method 3, Step 1 Step 2: 2,8,13-triazatricyclo[7.4.0.0 2,6]Trideca-1(9),3,5,10,12-pentaen-7-one Methyl 1-(3-nitro-2-pyridyl)pyrrole-2-carboxylate (0.50 g, 2.02 mmol) was dissolved in DCM (10 mL) and cooled to 0 °C. Trichlorosilane (0.71 mL, 7.08 mmol) was added, followed by dropwise addition of DIPEA (1.8 mL, 10.1 mmol) over 5 minutes. The reaction mixture was stirred at room temperature for 24 hours. The reaction was diluted with DCM (40 mL) and slowly added to saturated aqueous NaHCO (50 mL). [Note: Vigorous gas evolution occurred and the reaction became very foamy]. The mixture was stirred at room temperature for 30 minutes, then separated and extracted with DCM (2 × 25 mL). The combined organics were dried (MgSO) and concentrated to dryness to give methyl 1-(3-amino-2-pyridyl)pyrrole-2-carboxylate, which was used in the next step without further purification.

[0307] Methyl 1-(3-amino-2-pyridyl)pyrrole-2-carboxylate (439 mg, 2.02 mmol) was dissolved in acetic acid (10 mL) and heated for 30 minutes to 100° C. The reaction mixture was concentrated to dryness and triturated with water (2 mL) to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.27 (dd,J = 4.7, 1.4 Hz, 1H), 8.18 (dd,J = 2.7, 1.6 Hz, 1H), 7.72 (dd,J = 8.0, 1.5 Hz, 1H), 7.44 (dd,J = 8.0, 4.7 Hz, 1H), 7.16 (dd,J = 3.8, 1.5 Hz, 1H), 6.86 - 6.65 (m, 1H). Tr(METCR1410) = 0.86 min, (ES + ) (M+H) + 186.0, 90%.

[0308] Steps 3-5: Follow steps 3-5 of Method 2.

[0309] The following was also prepared by this route:

[0310] [Table 8] TIFF0007796054000086.tif240149TIFF0007796054000087.tif239150TIFF0007796054000088.tif239149TIFF0007796054000089.tif25149

[0311] Method 5 Scheme of Method 5

[0312] [ka]

[0313] [Example 5-1] Step 1: Follow the steps in Method 3, Step 1 Step 2: 4H,5H-Pyrrolo[1,2-a]quinoxalin-4-one Iron powder (4.38 g, 78.5 mmol) was added to a solution of methyl 1-(2-nitrophenyl)-1H-pyrrole-2-carboxylate (4.83 g, 19.6 mmol) in acetic acid (50 mL). The mixture was stirred at 100° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. 1N HCl (250 mL) was slowly added to the residue. The unreacted iron powder was collected with a magnetic bar, and the mixture was stirred for 30 minutes to remove any unreacted iron. The solid was collected by filtration, washed thoroughly with water, and dried in vacuo overnight. The crude product was dissolved in methanol (200 mL), stirred for 15 minutes, and filtered through Celite. The filtrate was concentrated under reduced pressure to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 11.25 (s, 1H), 8.18 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.28 (d, J = 6.1 Hz, 2H), 7.24 - 7.15 (m, 1H), 7.06 - 6.98 (m, 1H), 6.71 - 6.64 (m, 1H). Tr(MET-uHPLC-AB-101) = 2.01 min, (ES+ ) (M+H) + 185.1, 100%.

[0314] Steps 3-5: Follow steps 3-5 of Method 2. The following was also prepared by this route:

[0315] [Table 9] TIFF0007796054000092.tif222150TIFF0007796054000093.tif240149TIFF0007796054000094.tif240149 TIFF0007796054000095.tif240149TIFF0007796054000096.tif227151TIFF0007796054000097.tif207150

[0316] Method 6 Scheme of Method 6

[0317] [ka]

[0318] [Example 6-1] Step 1: Method 2, performed as in Step 1 Step 2: 2,8,12-triazatricyclo[7.4.0.0 2,6 ]Trideca-1(9),3,5,10,12-pentaen-7-one Sodium dithionite (10.13 g, 58.2 mmol) was added to a solution of methyl 1-(4-nitro-3-pyridyl)pyrrole-2-carboxylate (4.67 g, 14.5 mmol) in ethanol (60 mL) and water (60 mL), and the reaction mixture was stirred at 75° C. for 8 hours. The organic solvent was removed in vacuo, and the resulting aqueous solution was basified to pH 8 with saturated aqueous NaHCO. The solution was extracted with EtOAc (4×30 mL), and the combined organics were dried (NaSO), filtered, and concentrated in vacuo to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ 11.54 (s, 1H), 9.27 (s, 1H), 8.35 (d, J = 5.4 Hz, 1H), 8.31 (dd, J = 2.8, 1.4 Hz, 1H), 7.21 (d, J = 5.4 Hz, 1H), 7.10 (dd, J = 3.9, 1.4 Hz, 1H), 6.73 (dd, J = 3.8, 2.8 Hz, 1H). Tr(METCR1410) = 0.18 min, (ES + ) (M+H) + 186.0, 60%.

[0319] Steps 3-5: Follow steps 3-5 of Method 2. The following was also prepared by this route:

[0320] [Table 10] TIFF0007796054000100.tif186150

[0321] Method 7 Scheme of Method 7

[0322] [ka]

[0323] [Example 7-1] Step 1: 1-Chloro-7-fluoro-5H-pyrrolo[1,2-a]quinoxalin-4-one 7-Fluoro-5H-pyrrolo[1,2-a]quinoxalin-4-one (500 mg, 2.47 mmol) was suspended in THF (50 mL) and 1-chloropyrrolidine-2,5-dione (330 mg, 2.47 mmol) was added. The reaction mixture was heated to 60° C. overnight. The mixture was concentrated to dryness and partitioned between water and DCM. The organic layer was concentrated and purified by recrystallization from DMSO (50 mL) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 8.77 (dd,J = 9.2, 5.1 Hz, 1H), 7.34 - 6.94 (m, 3H), 6.76 (d,J = 4.2 Hz, 1H). Tr(METCR1410) = 1.08 minutes, (ES + ) (M+H) + 236.9, 89%.

[0324] Steps 2-3: Follow steps 3-4 of Method 3. The following was also prepared by this route:

[0325] [Table 11]

[0326] Method 8 Scheme of Method 8

[0327] [ka]

[0328] [Example 8-1] Step 1: N-(2,5-difluorophenyl)-1H-pyrazole-5-carboxamide 2,5-Difluoroaniline (864 mg, 6.69 mmol), 1H-pyrazole-5-carboxylic acid (500 mg, 4.46 mmol), and EDC hydrochloride (1710 mg, 8.92 mmol) were suspended in pyridine (40 mL), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through filter paper, and the filtrate was diluted with water, extracted with DCM (3x), dried (MgSO4), and concentrated to dryness. The product was evaporated to dryness in vacuo at 40 °C to give the title compound, which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H), 9.63 (s, 1H), 7.93 (s, 1H), 7.83 (s, 1H), 7.37 (ddd, J = 10.3, 9.2, 5.1 Hz, 1H), 7.05 (ddd, J = 12.1, 8.3, 3.4 Hz, 1H), 6.83 (s, 1H).

[0329] Step 2: 7-Fluoro-4H,5H-pyrazolo[1,5-a]quinoxalin-4-one N-(2,5-difluorophenyl)-1H-pyrazole-5-carboxamide (294 mg, 1.32 mmol) was dissolved in anhydrous DMF (8.82 mL) and sodium hydride (60%, 63 mg, 2.63 mmol) was added. The reaction was heated to 150° C. for 48 hours. An additional portion of sodium hydride (1 equivalent) was added and heating continued for an additional 24 hours at 150° C. The reaction was poured into ammonium chloride solution and the resulting precipitate was isolated by filtration, washed with water, and evaporated to dryness to provide the title compound. 1 H NMR (500 MHz, chloroform-d) δ 10.41 (s, 1H), 8.28 (dd, J = 9.0, 5.2 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.16–7.06 (m, 2H).

[0330] Step 3: 3-{7-fluoro-4-oxo-4H,5H-pyrazolo[1,5-a]quinoxalin-5-yl}propanoic acid 7-Fluoro-4H,5H-pyrazolo[1,5-a]quinoxalin-4-one (126 mg, 0.620 mmol) was dissolved in THF (6 mL) in a sealed tube, and sodium hydroxide (149 mg, 3.72 mmol) was added, followed by ethyl prop-2-enoate (0.33 mL, 3.10 mmol). The mixture was stirred at 60° C. for 72 h. The reaction mixture was concentrated to dryness, suspended in water (50 mL), and the pH was adjusted to pH 1 using 6 M HCl. The aqueous was extracted into EtOAc (3×), dried (MgSO4), and concentrated to give the desired product. The product was used without further purification. Tr(METCR1410) = 0.97 min, m / z (ES + ) (M+H) + 275.8, 50%.

[0331] Step 4: 3-{7-fluoro-4-oxo-4H,5H-pyrazolo[1,5-a]quinoxalin-5-yl}-N-(5-methoxypyridin-2-yl)propanamide 3-(7-Fluoro-4-oxo-pyrazolo[1,5-a]quinoxalin-5-yl)propanoic acid (100 mg, 0.182 mmol) was dissolved in DMF (1.5 mL), and then 5-methoxypyridin-2-amine (34 mg, 0.272 mmol), HATU (104 mg, 0.272 mmol), and DIPEA (0.10 mL, 0.545 mmol) were added, and the reaction was stirred at room temperature for 7 hours. The reaction mixture was purified by basic preparative HPLC to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.27 (dd, J = 9.0, 5.7 Hz, 1H), 8.09 (d, J = 2.1 Hz, 1H), 8.04 - 7.98 (m, 2H), 7.73 (dd, J = 11.2, 2.5 Hz, 1H), 7.43 (dd, J = 9.1, 3.0 Hz, 1H), 7.31 - 7.24 (m, 1H), 7.19 (d, J = 2.1 Hz, 1H), 4.58 - 4.52 (m, 2H), 3.80 (s, 3H), 2.79 (t, J = 7.3 Hz, 2H). 19F NMR (471 MHz, DMSO-d6) -113.24. Tr(MET-uHPLC-AB-101) = 2.67 min m / z (ES + ) (M+H) + 382.2, 97%.

[0332] The following was also prepared by this route:

[0333] [Table 12] TIFF0007796054000105.tif240149TIFF0007796054000106.tif227149TIFF0007796054000107.tif219150

[0334] Method 9 Scheme of Method 9

[0335] [ka]

[0336] [Example 9-1] Step 1: (E)-3-(Dimethylamino)-1-(4-fluoro-2-nitro-phenyl)prop-2-en-1-one 1-(4-Fluoro-2-nitro-phenyl)ethanone (300 mg, 1.64 mmol) was dissolved in 1,1-dimethoxy-N,N-dimethyl-methanamine (2.2 mL, 16.4 mmol) in a sealed tube and the reaction mixture was heated to 90° C. for 3 hours. The reaction mixture was concentrated in vacuo to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 7.91 (d,J = 7.3 Hz, 1H), 7.78 - 7.18 (m, 3H), 5.38 (s, 1H), 3.11 (d,J = 11.8 Hz, 3H), 2.88 (s, 3H). Tr(METCR1410) = 0.91 min, m / z (ES + ) (M+H) + 238.9, 92%.

[0337] Step 2: 5-(4-Fluoro-2-nitro-phenyl)-1-methyl-pyrazole Under a nitrogen atmosphere, methylhydrazine (0.19 mL, 3.58 mmol) was added to a solution of (E)-3-(dimethylamino)-1-(4-fluoro-2-nitro-phenyl)prop-2-en-1-one (310 mg, 1.30 mmol) in acetic acid (3.1 mL) in a pressure tube. The mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into a mixture of water / ethyl acetate. The aqueous layer was separated, and the organic layer was washed with water and brine and then dried (MgSO4). The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica, n-hexane / ethyl acetate) to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 8.16 (dd,J = 8.6, 2.6 Hz, 1H), 7.81 - 7.64 (m, 2H), 7.49 (d,J = 1.9 Hz, 1H), 6.30 (d,J = 1.9 Hz, 1H), 3.64 (s, 3H). Tr(METCR1410) = 0.73min, m / z (ES + ) (M+H) + 222.1, 95% and 3-(4-fluoro-2-nitro-phenyl)-1-methyl-pyrazole 1 H NMR (500 MHz, DMSO-d6) δ 7.89 (dd,J = 8.4, 2.7 Hz, 1H), 7.83 (dd,J = 8.7, 5.6 Hz, 1H), 7.78 (d,J = 2.3 Hz, 1H), 7.60 (td,J = 8.5, 2.7 Hz, 1H), 6.51 (d,J = 2.3 Hz, 1H), 3.85 (s, 3H). Tr(METCR1410) = 0.77 min, m / z (ES + ) (M+H) + 222.1, 100%.

[0338] Step 3: 5-Fluoro-2-(2-methylpyrazol-3-yl)aniline 5-(4-Fluoro-2-nitro-phenyl)-1-methyl-pyrazole (160 mg, 0.723 mmol) was dissolved in acetic acid (3.9 mL) and then iron (162 mg, 2.89 mmol) was added. The mixture was heated to 60° C. in a sealed tube for 5 h. The crude product mixture was concentrated in vacuo, and then the residue was stirred in a mixture of 1 M Na2CO3 (100 mL) and EtOAc (100 mL) for 1 h. The mixture was then filtered through glass fiber filter paper. The filtrate was separated, and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organics were dried (MgSO4) and concentrated to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 7.49 (d,J = 1.8 Hz, 1H), 7.01 (dd,J = 8.4, 6.8 Hz, 1H), 6.55 (dd,J = 11.7, 2.6 Hz, 1H), 6.41 (td,J = 8.5, 2.6 Hz, 1H), 6.25 (d,J = 1.8 Hz, 1H), 5.19 (s, 2H), 3.63 (s, 3H). Tr(METCR1410) = 0.68 min, m / z (ES + ) (M+H) + 192.1, 94%.

[0339] Step 4: 7-Fluoro-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one CDI (153 mg, 0.941 mmol) was added to a solution of 5-fluoro-2-(2-methylpyrazol-3-yl)aniline (90 mg, 0.471 mmol) in NMP (2 mL). The mixture was stirred at 150° C. for 30 min under microwave irradiation and then cooled to room temperature. The reaction mixture was diluted with water and extracted with DCM. The combined organics were dried (MgSO4) and concentrated to give the title compound. Tr(METCR1410) = 0.88 min, m / z (ES + ) (M+H) + 218.0, 96%.

[0340] Steps 5-6: Follow steps 3-4 of Method 3. The following was prepared by this route:

[0341] [Table 13] TIFF0007796054000110.tif239152TIFF0007796054000111.tif240151TIFF0007796054000112.t if240152TIFF0007796054000113.tif240152TIFF0007796054000114.tif239151TIFF00077960540 00115.tif241151TIFF0007796054000116.tif240151TIFF0007796054000117.tif240151TIFF000 7796054000118.tif240151TIFF0007796054000119.tif240151TIFF0007796054000120.tif202152

[0342] Method 10 Scheme of Method 10

[0343] [ka]

[0344] [Example 10-1] Step 1: N-(5-benzyloxy-2-pyridyl)-3-(7-fluoro-4-oxo-pyrrolo[1,2-a]quinoxalin-5-yl)propanamide 3-(7-Fluoro-4-oxo-pyrrolo[1,2-a]quinoxalin-5-yl)propanoic acid (prepared according to Method 3, 100 mg, 0.365 mmol) was dissolved in DMF (3 mL), followed by the addition of 5-(benzyloxy)pyridin-2-amine (110 mg, 0.547 mmol), HATU (208 mg, 0.547 mmol), and DIPEA (0.19 mL, 1.09 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water, extracted with EtOAc (3×), dried (MgSO4), and concentrated to dryness. The residue was triturated with DCM / MeOH to give the title compound.1 H NMR (500 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.21 - 8.19 (m, 1H), 8.18 - 8.15 (m, 1H), 8.07 (d, J = 3.0 Hz, 1H), 8.01 (d, J = 8.9 Hz, 1H), 7.57 (dd, J = 11.3, 2.6 Hz, 1H), 7.50 (dd, J = 9.1, 3.1 Hz, 1H), 7.45 (d, J = 7.0 Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.37 - 7.31 (m, 1H), 7.20 - 7.13 (m, 1H), 7.06 (dd, J = 3.9, 1.4 Hz, 1H), 6.70 (dd, J = 3.8, 2.8 Hz, 1H), 5.15 (s, 2H), 4.52 - 4.42 (m, 2H), 2.75 (t, J = 7.4 Hz, 2H). 1.19 min m / z (ES + ) (M+H) + 457.1, 95%.

[0345] Step 2: 3-{7-fluoro-4-oxo-4H,5H-pyrrolo[1,2-a]quinoxalin-5-yl}-N-(5-hydroxypyridin-2-yl)propanamide N-[5-(benzyloxy)pyridin-2-yl]-3-{7-fluoro-4-oxo-4H,5H-pyrrolo[1,2-a]quinoxalin-5-yl}propanamide (90 mg, 0.197 mmol) was dissolved in methanol (5 mL) and THF (5 mL) and placed under an inert atmosphere. Pd / C (10%, 10 mg, 0.197 mmol) was added, and the reaction was placed under a hydrogen atmosphere and stirred at room temperature for 3 hours. The reaction mixture was filtered through Celite, washed with MeOH, and the filtrate was concentrated to dryness to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.63 (br. s, 1H), 8.22 - 8.13 (m, 2H), 7.90 (d, J = 8.9 Hz, 1H), 7.82 (d, J = 2.9 Hz, 1H), 7.56 (dd, J = 11.3, 2.6 Hz, 1H), 7.21 - 7.12 (m, 2H), 7.06 (dd, J = 3.9, 1.4 Hz, 1H), 6.69 (dd, J = 3.8, 2.8 Hz, 1H), 4.54 - 4.36 (m, 2H), 2.82 - 2.64 (m, 2H). Tr(MET-uHPLC-AB-101) = 2.16 min m / z (ES + ) (M+H) + 367.2, 100%.

[0346] Method 11 Scheme of Method 11

[0347] [ka]

[0348] [Example 11-1] Step 1: 3-[(5-methoxy-2-pyridyl)oxy]propan-1-ol Sodium hydride (60%, 0.17 g, 4.33 mmol) and propane-1,3-diol (269 mg, 3.54 mmol) were dissolved in DMF (5 mL), and 2-fluoro-5-methoxypyridine (0.50 g, 3.93 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The residue was partitioned between DCM (10 mL) and water (10 mL) and extracted with DCM (2 × 5 mL). The combined organic extracts were dried and concentrated. Further purification by column chromatography (silica, EtOAc-heptane mixtures) afforded the title compound. 1H NMR (500 MHz, DMSO-d6) δ 7.83 (d,J = 3.1 Hz, 1H), 7.37 (dd,J = 8.9, 3.1 Hz, 1H), 6.74 (d,J = 8.9 Hz, 1H), 4.50 (t,J = 5.1 Hz, 1H), 4.23 (t,J = 6.5 Hz, 2H), 3.76 (s, 3H), 3.53 (q,J = 6.2 Hz, 2H), 2.00 - 1.51 (m, 2H). Tr(METCR1410) = 0.78 min, (ES) + [M+H] + = 184.1, 99%.

[0349] Step 2: 2-(3-chloropropoxy)-5-methoxy-pyridine 3-[(5-Methoxy-2-pyridyl)oxy]propan-1-ol (100 mg, 0.546 mmol) was dissolved in DCM (5 mL) and thionyl chloride (0.080 mL, 1.09 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to give the title compound. Tr(METCR1410) = 1.10 min, (ES) + [M+H] + = 202.1 / 204.1, 100%.

[0350] Step 3: 7-Fluoro-5-{3-[(5-methoxypyridin-2-yl)oxy]propyl}-4H,5H-pyrrolo[1,2-a]quinoxalin-4-one 7-Fluoro-5H-pyrrolo[1,2-a]quinoxalin-4-one (50 mg, 0.248 mmol), K2CO3 (137 mg, 0.992 mmol) and potassium iodide (165 mg, 0.992 mmol) were dissolved in DMF (5 mL) and 2-(3-chloropropoxy)-5-methoxy-pyridine (100 mg, 0.496 mmol) was added. The reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was heated at 60 °C for 4 hours. The reaction mixture was concentrated in vacuo and triturated with water (5 mL). Further purification by column chromatography (silica, EtOAc-heptane mixtures) gave the title compound. 1H NMR (500 MHz, DMSO-d6) δ 8.30 - 8.05 (m, 2H), 7.45 - 7.32 (m, 2H), 7.28 (dd, J = 9.8, 3.3 Hz, 1H), 7.23 - 7.12 (m, 1H), 7.05 (dd, J = 3.9, 1.4 Hz, 1H), 6.70 (dd, J = 3.8, 2.8 Hz, 1H), 6.34 (d, J = 9.8 Hz, 1H), 4.24 (t, J = 7.3 Hz, 2H), 4.12 - 3.84 (m, 2H), 3.64 (s, 3H), 2.13 - 1.89 (m, 2H). 19 F NMR (376 MHz, DMSO-d6) -115.09. Tr(METCR1603) = 3.53 min m / z (ES + ) (M+H) + 368.1, 97%.

[0351] Method 12 Scheme of Method 12

[0352] [ka]

[0353] [Example 12-1] Step 1: 5-(2-azidoethyl)-7-fluoro-pyrrolo[1,2-a]quinoxalin-4-one 7-Fluoro-5H-pyrrolo[1,2-a]quinoxalin-4-one (300 mg, 1.48 mmol) was added to a stirred suspension of sodium hydride (60%, 59 mg, 1.48 mmol) in DMF (3.5 mL) at room temperature. After 30 minutes, a solution of 2-azidoethyl 4-methylbenzenesulfonate (358 mg, 1.48 mmol) in DMF (0.5 mL) was added dropwise. The reaction was stirred under nitrogen at 80° C. for 24 hours. After this time, additional 2-azidoethyl 4-methylbenzenesulfonate (120 mg, 0.48 mmol) was added, and the reaction was stirred at 80° C. for another 24 hours. The reaction was diluted with water and triturated for 30 minutes. The solid was filtered, dried, and purified by column chromatography (silica, 0-50% EtOAc in heptane) to provide the title compound. 1 H NMR (500 MHz, chloroform-d) δ 7.67 (dd, J = 9.0, 5.2 Hz, 1H), 7.61 (dd, J = 2.8, 1.5 Hz, 1H), 7.26 - 7.23 (m, 1H), 7.15 (dd, J = 10.5, 2.6 Hz, 1H), 6.98 (ddd, J = 9.0, 7.5, 2.6 Hz, 1H), 6.68 (dd, J = 3.9, 2.8 Hz, 1H), 4.39 (t, J = 6.4 Hz, 2H), 3.73 (t, J = 6.4 Hz, 2H). Tr(METCR0990) = 1.56 minutes, (ES + ) [M+H] + 272.1, 100%.

[0354] Step 2: N-[2-(7-fluoro-4-oxo-pyrrolo[1,2-a]quinoxalin-5-yl)ethyl]-4-methyl-benzamide Triphenylphosphine (235 mg, 0.896 mmol) was added to a solution of 5-(2-azidoethyl)-7-fluoro-pyrrolo[1,2-a]quinoxalin-4-one (81 mg, 0.299 mmol) in THF (2 mL) and water (0.2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction was evaporated to dryness and then dissolved in pyridine (2 mL). 4-Methylbenzoyl chloride (51 mg, 0.328 mmol) and DMAP (7.3 mg, 0.0597 mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. The reaction was concentrated to dryness and purified by preparative HPLC (MeCN-water, 0.1% formic acid) to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (t, J = 5.8 Hz, 1H), 8.20 (dd, J = 2.8, 1.5 Hz, 1H), 8.17 (dd, J = 9.1, 5.5 Hz, 1H), 7.72 (dd, J = 11.4, 2.6 Hz, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 7.9 Hz, 2H), 7.18 - 7.12 (m, 1H), 7.06 (dd, J = 3.9, 1.5 Hz, 1H), 6.70 (dd, J = 3.9, 2.8 Hz, 1H), 4.32 (t, J = 6.9 Hz, 2H), 3.54 (q, J = 6.5 Hz, 2H), 2.34 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ -115.19. Tr(MET-uPLC-AB-101) = 3.17 min, (ES + ) [M+H] + 364.2, 100%.

[0355] The following was also prepared by this route:

[0356] [Table 14]

[0357] Method 13 Method 13 scheme

[0358] [ka]

[0359] [Example 13-1] Step 1: 2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethanol 1,2,3,4-Tetrahydroisoquinoline (500 mg, 3.68 mmol), K2CO3 (508 mg, 3.68 mmol), and 2-bromoethanol (460 mg, 3.68 mmol) were dissolved in acetonitrile (50 mL) and heated to 60 °C for 4 h. The reaction mixture was concentrated to dryness and partitioned between DCM (25 mL) and water (25 mL). The organic extract was dried (MgSO4), filtered, and concentrated to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 7.52 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 3.94 - 3.79 (m, 2H), 3.75 (t, J = 8.8 Hz, 1H), 3.70 (s, 3H), 2.41 - 2.31 (m, 2H), 2.29 (s, 3H)

[0360] Step 2: 2-(2-chloroethyl)-3,4-dihydro-1H-isoquinoline 2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethanol (50 mg, 0.282 mmol) was dissolved in DCM (5 mL) and thionyl chloride (0.041 mL, 0.564 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. An additional portion of thionyl chloride (0.041 mL, 0.564 mmol) was added and the reaction mixture was stirred at room temperature for another 3 hours. The reaction mixture was concentrated to dryness to give the title compound. The product was carried forward without further purification.

[0361] Step 3: 7-Fluoro-5-[2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-4H,5H-pyrrolo[1,2-a]quinoxalin-4-one 7-Fluoro-5H-pyrrolo[1,2-a]quinoxalin-4-one (100 mg, 0.495 mmol), K2CO3 (273 mg, 1.98 mmol), and potassium iodide (328 mg, 1.98 mmol) were dissolved in DMF (5 mL), and 2-(2-chloroethyl)-3,4-dihydro-1H-isoquinoline (194 mg, 0.989 mmol) was added. The reaction mixture was heated at 60 °C for 4 hours. The reaction mixture was concentrated in vacuo and triturated with water (5 mL). Further purification by basic preparative HPLC gave the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 8.32 - 8.08 (m, 2H), 7.50 (dd, J = 11.3, 2.6 Hz, 1H), 7.32 - 6.92 (m, 6H), 6.68 (dd, J = 3.8, 2.8 Hz, 1H), 4.43 (t, J = 6.7 Hz, 2H), 3.66 (s, 2H), 2.92 - 2.63 (m, 6H). 19 F NMR (376 MHz, DMSO-d6) -115.14. Tr(MET-uHPLC-AB-101) = 1.78 min m / z (ES + ) (M+H) + 362.2, 100%.

[0362] The following was also prepared by this route:

[0363] [Table 15]

[0364] Method 14 Scheme of Method 14

[0365] [ka]

[0366] [Example 14-1] Step 1: tert-butyl N-[2-(1H-pyrrole-2-carbonylamino)ethyl]carbamate 1H-Pyrrole-2-carboxylic acid (1.00 g, 9.00 mmol) was dissolved in DMF (25 mL), purged with nitrogen, and stirred at room temperature. DIPEA (1.6 mL, 9.00 mmol) and HATU (5.13 g, 13.5 mmol) were added to the reaction mixture and stirred for 10 minutes. tert-Butyl N-(2-aminoethyl)carbamate (2.94 g, 18.0 mmol) was then added to the reaction mixture and stirred for 1 hour. The solvent was removed under reduced pressure. The residue was suspended in water and washed with DCM (3 x 25 mL). The aqueous solution was concentrated and purified by column chromatography (silica, EtOAc-heptane mixture) to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 11.42 (s, 1H), 7.99 (t, J = 5.6 Hz, 1H), 7.03 - 6.53 (m, 3H), 6.07 (dt, J = 3.5, 2.4 Hz, 1H), 3.23 (q, J = 6.4 Hz, 2H), 3.06 (q, J = 6.3 Hz, 2H), 1.38 (s, 9H). Tr(METCR1410) = 0.93 min, (ES) + [M+H] + = 275.9, 100%.

[0367] Step 2: tert-Butyl N-[2-(4-oxopyrrolo[1,2-a]quinoxalin-5-yl)ethyl]carbamate Cs2CO3 (1.49 g, 4.56 mmol) and 1-fluoro-2-nitro-benzene (225 mg, 1.56 mmol) were dissolved in acetonitrile (5 mL) and tert-butyl N-[2-(1H-pyrrole-2-carbonylamino)ethyl]carbamate (330 mg, 1.30 mmol) was added. The reaction mixture was heated to 60 °C overnight. The reaction mixture was concentrated. The residue was partitioned between water (5 mL) and EtOAc (5 mL) and extracted with EtOAc (2 × 5 mL). The combined organics were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica, EtOAc-heptane mixtures) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 1.2 Hz, 1H), 8.13 (d, J = 7.0 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.33 - 7.13 (m, 1H), 7.11 - 6.82 (m, 2H), 6.70 (dd, J = 3.8, 2.8 Hz, 1H), 4.25 (t, J = 6.6 Hz, 2H), 3.24 (d, J = 6.8 Hz, 2H), 1.33 (s, 9H). Tr(METCR1410) = 1.10 minutes, (ES) + [M+Na] + = 350.0, 91%.

[0368] Step 3: 5-(2-aminoethyl)pyrrolo[1,2-a]quinoxalin-4-one hydrochloride Tert-butyl N-[2-(4-oxopyrrolo[1,2-a]quinoxalin-5-yl)ethyl]carbamate (100 mg, 0.305 mmol) was dissolved in 4 M HCl in dioxane (10 mL) and stirred at room temperature for 2 hours. The reaction mixture was filtered to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (dd, J = 2.8, 1.5 Hz, 1H), 8.17 (dd, J = 8.1, 1.4 Hz, 1H), 7.99 (s, 3H), 7.79 - 7.57 (m, 1H), 7.42 (td, J = 8.4, 7.9, 1.4 Hz, 1H), 7.37 - 7.18 (m, 1H), 7.09 (dd, J = 3.9, 1.5 Hz, 1H), 6.73 (dd, J = 3.8, 2.8 Hz, 1H), 4.51 (t, J = 6.6 Hz, 2H), 3.11 (q, J = 6.1 Hz, 2H). Tr(METCR1410) = 0.93 minutes, (ES) + [M+H] + = 275.9, 100%.

[0369] Step 4: 5-Methoxy-N-(2-{4-oxo-4H,5H-pyrrolo[1,2-a]quinoxalin-5-yl}ethyl)pyridine-2-carboxamide 5-Methoxypyridine-2-carboxylic acid (0.023 mL, 0.0948 mmol) was dissolved in DMF (1 mL), and HATU (54 mg, 0.142 mmol) and DIPEA (0.050 mL, 0.284 mmol) were added, followed by 5-(2-aminoethyl)pyrrolo[1,2-a]quinoxalin-4-one hydrochloride (25 mg, 0.095 mmol). The reaction mixture was stirred at room temperature for 30 minutes. Purification by basic preparative HPLC afforded the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 8.99 (t, J = 6.0 Hz, 1H), 8.29 (d, J = 2.8 Hz, 1H), 8.23 ​​- 8.17 (m, 1H), 8.12 (d, J = 7.1 Hz, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.53 (dd, J = 8.7, 2.9 Hz, 1H), 7.43 - 7.31 (m, 1H), 7.32 - 7.15 (m, 1H), 7.05 (dd, J = 3.8, 1.3 Hz, 1H), 6.84 - 6.49 (m, 1H), 4.38 (t, J = 6.9 Hz, 2H), 3.90 (s, 3H), 3.70 - 3.47 (m, 2H). Tr(MET-uHPLC-AB-101) = 2.79 min m / z (ES + ) (M+H) + 363.2, 100%.

[0370] The following was also prepared by this route:

[0371] [Table 16]

[0372] Method 15 Scheme of Method 15

[0373] [ka]

[0374] [Example 15-1] Step 1: 2-[2-(7-fluoro-4-oxo-pyrrolo[1,2-a]quinoxalin-5-yl)ethyl]isoindoline-1,3-dione 7-Fluoro-5H-pyrrolo[1,2-a]quinoxalin-4-one (500 mg, 2.47 mmol) was suspended in DMF (25 mL). KCO (410 mg, 2.97 mmol) and potassium iodide (493 mg, 2.97 mmol) were added, followed by 2-(2-chloroethyl)-1H-isoindole-1,3(2H)-dione (622 mg, 2.97 mmol). The reaction mixture was heated to 60 °C overnight and then to 80 °C for 2 days. The reaction mixture was concentrated to dryness. The residue was partitioned between water (25 mL) and DCM (25 mL) and extracted with DCM (2 × 10 mL). The combined organics were dried (MgSO), filtered, and concentrated. Purification by column chromatography (silica, EtOAc-heptane mixtures) afforded the title compound. Tr(METCR1410) = 1.18 min, m / z (ES + ) (M+H) + 376.0, 25%.

[0375] Step 2: 5-(2-aminoethyl)-7-fluoro-pyrrolo[1,2-a]quinoxalin-4-one 2-[2-(7-Fluoro-4-oxo-pyrrolo[1,2-a]quinoxalin-5-yl)ethyl]isoindoline-1,3-dione (510 mg, 0.340 mmol) was dissolved in dry EtOH (1.4167 mL). Hydrazine hydrate (0.039 mL, 0.679 mmol) was added, and the solution was heated at 50° C. for 30 minutes. The mixture was quenched with concentrated HCl (2 mL) and stirred for 10 minutes. The white solid was filtered off and washed with EtOH (2×10 mL). The filtrate was concentrated under reduced pressure, and the remaining aqueous solution was adjusted to pH >7 with 2 M NaOH. After extraction with EtOAc (2×30 mL), the combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give the title compound. Tr(METCR1410) = 0.78 min, m / z (ES + ) (M+H) + 246.0, 43%.

[0376] Step 3: Follow the same steps as in Step 4 of Method 14. The following was prepared by this route:

[0377] [Table 17]

[0378] Method 16 Scheme of Method 16

[0379] [ka]

[0380] [Example 16-1] Step 1: 5-(1,3-dioxolan-2-ylmethyl)-7-fluoro-1-methyl-pyrazolo[4,3-c]quinolin-4-one 7-Fluoro-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one (prepared according to Method 9, 500 mg, 2.30 mmol) and K2CO3 (445 mg, 3.22 mmol) were dissolved in DMF (50 mL) and 2-(bromomethyl)-1,3-dioxolane (436 mg, 2.53 mmol) was added. The reaction mixture was heated to 60 °C for 24 h. K2CO3 (445 mg, 3.22 mmol) and 2-(bromomethyl)-1,3-dioxolane (436 mg, 2.53 mmol) were added, and the reaction mixture was heated to 60 °C for an additional 3 days. The reaction mixture was concentrated in vacuo and partitioned between DCM (50 mL) and water (50 mL). The organic phase was separated, dried (MgSO4), filtered, and concentrated in vacuo. Further purification by column chromatography (silica, EtOAc-heptane mixtures) afforded the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (dd, J = 9.0, 6.3 Hz, 1H), 8.13 (s, 1H), 7.67 (dd, J = 12.4, 2.4 Hz, 1H), 7.26 (m, 1H), 5.13 (t, J = 4.5 Hz, Tr(METCR1410) = 1.01 min, m / z (ES + ) (M+H) + 304.0, 100%.

[0381] Step 2: 2-(7-fluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)acetaldehyde 5-(1,3-Dioxolan-2-ylmethyl)-7-fluoro-1-methyl-pyrazolo[4,3-c]quinolin-4-one (140 mg, 0.462 mmol) was dissolved in THF (4 mL) and 2 M hydrogen chloride (2.3 mL, 4.62 mmol) was added. The mixture was heated to 60 °C overnight. The solvent was removed in vacuo and the residue was partitioned between DCM and water. The organic phase was dried (MgSO), filtered and concentrated to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.35 (dd, J = 9.0, 6.2 Hz, 1H), 8.16 - 8.08 (m, 1H), 7.48 (dd, J = 12.1, 2.4 Hz, 1H), 7.29 - 7.24 (m, 1H), 5.34 (s, 2H), 4.38 (s, 3H).

[0382] Step 3: 5-[2-(benzylamino)ethyl]-7-fluoro-1-methyl-pyrazolo[4,3-c]quinolin-4-one A solution of 2-(7-fluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)acetaldehyde (120 mg, 0.463 mmol) and 1-phenylmethanamine (55 mg, 0.509 mmol) in DCM (4 mL) was treated with acetic acid (0.11 mL) and stirred for 1 h, then STAB (157 mg, 0.741 mmol) was added portionwise and stirred for an additional 4 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between DCM and water. The organic layer was dried (MgSO), filtered, and concentrated in vacuo. Further purification by SCX cartridge afforded the title compound. Tr(METCR1410) = 0.89 min, m / z (ES + ) (M+H) + 351.4, 93%.

[0383] Step 4: 5-(2-aminoethyl)-7-fluoro-1-methyl-pyrazolo[4,3-c]quinolin-4-one 5-[2-(benzylamino)ethyl]-7-fluoro-1-methyl-pyrazolo[4,3-c]quinolin-4-one (90 mg, 0.257 mmol) was dissolved in ethanol (9 mL) and palladium on carbon (10%, 27 mg, 0.0257 mmol) was added. The mixture was stirred under H2 atmosphere at room temperature for 4 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound. Tr(METCR1410) = 0.71 min, m / z (ES + ) (M+H) + 260.8, 93%.

[0384] Step 5: Follow the same steps as in Step 4 of Method 14 The following was prepared by this route:

[0385] [Table 18]

[0386] Method 17 Scheme of Method 17

[0387] [ka]

[0388] [Example 17-1] Steps 1-2: Follow steps 1-2 of Method 14. Steps 3-4: Follow steps 4-5 of Method 2 In this way the following was prepared: (1SR,2SR)-N-(5-Methoxypyridin-2-yl)-2-{4-oxo-4H,5H-pyrrolo[1,2-a]quinoxalin-5-yl}cyclobutane-1-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.16 (dd, J = 2.8, 1.5 Hz, 1H), 8.12 - 8.03 (m, 2H), 7.98 (d, J = 2.8 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.49 - 7.31 (m, 2H), 7.32 - 7.18 (m, 1H), 7.02 (dd, J = 3.8, 1.5 Hz, 1H), 6.68 (dd, J = 3.8, 2.8 Hz, 1H), 5.50 - 5.08 (m, 1H), 4.81 - 4.31 (m, 1H), 3.78 (s, 3H), 2.82 - 2.68 (m, 1H), 2.43 - 2.27 (m, 1H), 2.30 - 2.08 (m, 1H), 2.02 - 1.82 (m, 1H). Tr(MET-uHPLC-AB-101) = 3.02 min m / z (ES + ) (M+H) + 389.2, 100%.

[0389] Method 18 Scheme of Method 18

[0390] [ka]

[0391] [Example 18-1] Step 1: tert-butyl-[3-(6-methoxy-3-pyridyl)propoxy]-dimethyl-silane A mixture of 1,2-dimethoxyethane-dibromonickel (1:1) (40 mg, 0.13 mmol), 4,4'-dimethoxy-2,2'-bipyridine (28 mg, 0.13 mmol), and sodium iodide (155 mg, 1.03 mmol) in DMA (5 mL) was sonicated for 5 minutes and degassed with N2. The solution was transferred to a 10 mL Electrasyn vial equipped with an RVC cathode and a zinc anode. 5-Bromo-2-methoxypyridine (240 mg, 1.28 mmol) was added, followed by 3-bromopropoxy-tert-butyl-dimethyl-silane (438 mg, 1.66 mmol). A constant current of 10 mA was passed through the solution for 20 hours. The reaction was diluted with EtOAc (40 mL) and washed with water (50 mL). The aqueous layer was further extracted with EtOAc (2 × 40 mL). The combined organic layers were washed with brine, dried (MgSO), filtered and concentrated. The crude product was adsorbed onto silica and purified by column chromatography (silica, 0-20% EtOAc in heptane) to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 1.9 Hz, 1H), 7.52 (dd, J = 8.5, 2.5 Hz, 1H), 6.71 (d, J = 8.5 Hz, 1H), 3.78 (s, 3H), 3.60 - 3.48 (m, 2H), 2.60 - 2.49 (m, 2H), 1.81 - 1.63 (m, 2H), 0.85 (s, 9H), -0.01 (s, 6H). Tr(METCR1410) = 1.55 min, (ES + ) [M+H] + 282, 92%.

[0392] Step 2: 3-(6-Methoxy-3-pyridyl)propan-1-ol 4 M Hydrogen chloride in dioxane (0.77 mL, 3.06 mmol) was added to a solution of tert-butyl-[3-(6-methoxy-3-pyridyl)propoxy]-dimethyl-silane (224 mg, 0.56 mmol) in THF (5 mL) and stirred at room temperature. The reaction was diluted with saturated aqueous NaHCO and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried (MgSO), filtered, and concentrated. The crude product was purified by column chromatography (silica, 10-100% EtOAc in heptane) to give the title compound. 1 H NMR (500 MHz, chloroform-d) δ 7.99 (d, J = 2.3 Hz, 1H), 7.42 (dd, J = 8.5, 2.5 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 3.91 (s, 3H), 3.68 (t, J = 5.8 Hz, 2H), 2.70 - 2.57 (m, 2H), 1.96 - 1.73 (m, 2H), 1.35 (s, 1H). Tr(METCR1410) = 0.67 min, (ES + ) [M+H] + 168, 100%.

[0393] Step 3: 5-(3-chloropropyl)-2-methoxy-pyridine Thionyl chloride (68 μL, 0.957 mmol) was added to a solution of 3-(6-methoxy-3-pyridyl)propan-1-ol (20 mg, 0.120 mmol) in DCM (1 mL) cooled to 0° C. The mixture was allowed to warm to room temperature over 6 hours. The reaction mixture was concentrated to give the title compound, which was used in the next step without further purification. Tr(METCR1410) = 1.11 min, (ES + ) [M+H] + 186, 100%.

[0394] Step 4: 7-Fluoro-5-[3-(6-methoxy-3-pyridyl)propyl]pyrrolo[1,2-a]quinoxalin-4-one 7-Fluoro-5H-pyrrolo[1,2-a]quinoxalin-4-one (12 mg, 0.059 mmol), K2CO3 (33 mg, 0.237 mmol), and potassium iodide (39 mg, 0.237 mmol) were dissolved in DMF (1 mL), and 5-(3-chloropropyl)-2-methoxy-pyridine (22 mg, 0.119 mmol) was added. The reaction mixture was stirred at 60 °C overnight. The reaction was partitioned between DCM and water and extracted through a Telos phase separator. The aqueous layer was extracted twice more, and the combined organic layers were concentrated. The crude product was purified by acidic preparative HPLC to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 8.22 - 8.10 (m, 2H), 8.02 (d, J = 2.2 Hz, 1H), 7.59 (dd, J = 8.5, 2.5 Hz, 1H), 7.37 (dd, J = 11.2, 2.6 Hz, 1H), 7.21 - 7.10 (m, 1H), 7.03 (dd, J = 3.9, 1.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.68 (dd, J = 3.8, 2.8 Hz, 1H), 4.26 - 4.14 (m, 2H), 3.80 (s, 3H), 2.66 (t, J = 7.6 Hz, 2H), 1.89 (p, J = 7.7 Hz, 2H). 19 F NMR (471 MHz, DMSO-d6) δ -104.51 - -121.69 (m). Tr(MET-uHPLC-AB-101) = 3.24 min m / z (ES + ) (M+H) + 352.1, 100%.

[0395] Method 19 Scheme of Method 19

[0396] [ka]

[0397] [Examples 19-1 and 19-2] Steps 1-5: Follow steps 2-6 of Method 9. Step 6: N-(2,4-difluorophenyl)-3-(7-fluoro-4-oxo-1H-pyrazolo[4,3-c]quinolin-5-yl)propanamide Ammonium formate (89 mg, 1.44 mmol) and palladium(II) hydroxide (20%, 26 mg, 0.0374 mmol) were added to a solution of 3-(1-benzyl-7-fluoro-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)-N-(2,4-difluorophenyl)propanamide (137 mg, 0.288 mmol) in formic acid (10 mL). The reaction was stirred in a sealed tube at 60° C. for 2 hours. The reaction was allowed to cool to room temperature, diluted with MeOH (130 mL), filtered through Celite, and concentrated in vacuo. The residue was triturated with a minimum volume of MeOH to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 14.15 (s, 1H), 9.86 (s, 1H), 8.87 - 8.03 (m, 2H), 7.79 (m, 1H), 7.69 - 7.46 (m, 1H), 7.38 - 7.12 (m, 2H), 7.06 (t, J = 7.9 Hz, 1H), 4.54 (t, J = 7.0 Hz, 2H), 2.76 (t, J = 7.3 Hz, 2H). 19 F NMR (376 MHz, DMSO-d6) δ -108.47 (s), -114.82 (d, J = 5.0 Hz), -119.55 (d, J = 5.1 Hz). Tr(MET-uHPLC-AB-101) = 2.59 min, m / z (ES + ) (M+H) + 387.1, 99%.

[0398] Step 7: N-(2,4-difluorophenyl)-3-(7-fluoro-2-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)propanamide A solution of iodomethane (2.4 μL, 0.039 mmol) in anhydrous DMSO (0.5 mL) was added to a stirred mixture of N-(2,4-difluorophenyl)-3-(7-fluoro-4-oxo-1H-pyrazolo[4,3-c]quinolin-5-yl)propanamide (5.0 mg, 0.013 mmol) and CsCO (6.3 mg, 0.020 mmol) in anhydrous DMSO (0.5 mL). The reaction was stirred at room temperature for 1.5 hours. The reaction was concentrated and purified by acidic preparative HPLC to give each of the regioisomeric title compounds. Example 19-2: 1 H NMR (500 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.61 (s, 1H), 8.13 (dd, J = 8.6, 6.6 Hz, 1H), 7.79 (td, J = 9.0, 6.3 Hz, 1H), 7.53 (dd, J = 12.3, 2.2 Hz, 1H), 7.29 (ddd, J = 11.6, 9.0, 2.9 Hz, 1H), 7.16 (td, J = 8.5, 2.3 Hz, 1H), 7.11 - 6.97 (m, 1H), 4.52 (t, J = 7.4 Hz, 2H), 4.08 (s, 3H), 2.76 (s, 2H). 19 F NMR (376 MHz, DMSO-d6) δ -110.01 (s), -114.84 (d, J = 5.0 Hz), -119.49 (d, J = 5.1 Hz). Tr(MET-uHPLC-AB-101) = 2.85 min, m / z (ES + ) (M+H) + 401.2, 100%.

[0399] Characterization data for Examples 9-18 have been previously provided. The following was also prepared by this route:

[0400] [Table 19]

[0401] Method 20 Method 20 scheme

[0402] [ka]

[0403] [Example 20-1] Step 1: Benzyl 2,3,3-trideuterioprop-2-enoate K2CO3 (999 mg, 7.23 mmol) was added to a solution of acrylic acid-d4 (500 mg, 6.57 mmol) in DMF (5 mL). Benzyl bromide (0.78 mL, 6.57 mmol) in DMF (1 mL) was added dropwise at room temperature. The reaction was stirred at room temperature for 6 hours. The reaction was diluted with EtOAc (10 mL) and washed with water (3 x 2 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 7.41 - 7.30 (m, 5H), 5.19 (s, 2H). Tr(METCR1704) = 0.87 min, m / z (ES) + No mass ions were observed, 95%.

[0404] Step 2: 2,3,3-trideuterio-3-(7-fluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)propanoic acid 7-Fluoro-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one (100 mg, 0.460 mmol), 2 M sodium hydroxide (0.23 mL, 0.460 mmol), benzyl 2,3,3-trideuterioprop-2-enoate (114 mg, 0.691 mmol), tetrabutylammonium bromide (74 mg, 0.230 mmol), and THF (5 mL) were combined in a pressure tube and stirred at 50 °C for 1 h. The reaction mixture was diluted with water (3 mL) and extracted with EtOAc (10 mL). The organic fraction was concentrated in vacuo. KCO (64 mg, 0.460 mmol), THF (2 mL), and methanol (2 mL) were added to the residue. The reaction was stirred at room temperature for 0.5 h and concentrated in vacuo. The residue was acidified to pH 3 using 2M HCl, and the resulting precipitate was collected and dried by vacuum filtration to give the title compound. The filtrate was extracted with chloroform:IPA (3:1, 3 x 5 mL). The combined organics were dried using a separatory cartridge and concentrated in vacuo along with the original precipitate to give the title compound. Tr(MET-uHPLC-AB-101) = 3.00 min, m / z (ES + )(M+H) + 293.1, 17%.

[0405] Step 3: (N-(2,4-difluorophenyl)-3-{7-fluoro-1-methyl-4-oxo-1H,4H,5H-pyrazolo[4,3-c]quinolin-5-yl}(2,3,3-2H3)propanamide A solution of 2,3,3-trideuterio-3-(7-fluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)propanoic acid (17%, 140 mg, 0.07 mmol), 2,4-difluoroaniline (10 mg, 0.08 mmol), and EDC.HCl (21 mg, 0.11 mmol) in pyridine (3 mL) was stirred overnight at room temperature. The solvent was removed in vacuo, and the residue was purified by column chromatography. The product-containing fractions were concentrated in vacuo, and the residue was further purified by trituration with ethanol to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.34 (dd, J = 9.0, 6.2 Hz, 1H), 8.14 (s, 1H), 7.86 - 7.76 (m, 1H), 7.65 (dd, J = 12.2, 2.4 Hz, 1H), 7.36 - 7.23 (m, 2H), 7.11 - 7.02 (m, 1H), 4.36 (s, 3H), 2.73 (s, 1H). 19 F NMR (471 MHz, DMSO-d6) δ -108.57 - -108.87 (m), -114.85 (ddd, J = 14.3, 8.6, 6.0 Hz), -119.60 (td, J = 9.8, 5.5 Hz). Tr(MET-uHPLC-AB-101) = 2.82 min, m / z (ES + )(M+H) + 404.2, 87%.

[0406] Method 21 Method 21 scheme

[0407] [ka]

[0408] [Example 21-1] Step 1: 4,5-Difluoro-2-(2-methylpyrazol-3-yl)aniline The reactions were carried out as 2 x 250 mg reactions in separate reaction tubes. The reactions were carried out in parallel and under identical conditions as follows. Upon completion, the reactions were combined and purified together. 2-Bromo-4,5-difluoroaniline (0.30 mL, 2.40 mmol) was dissolved in 1,4-dioxane (22.838 mL) and water (2.2838 mL), and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (750 mg, 3.61 mmol) was added. The mixture was degassed for 5 minutes, and then Pd(PPh3)4 (278 mg, 0.240 mmol) was added. The reaction was heated in a sealed tube at 85 °C for 18 hours. The mixture was allowed to cool to room temperature, then concentrated in vacuo onto silica. Purification by flash column chromatography afforded the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 7.47 (d, J = 1.8 Hz, 1H), 7.09 (dd, J = 11.3, 9.1 Hz, 1H), 6.71 (dd, J = 13.2, 7.5 Hz, 1H), 6.27 (d, J = 1.9 Hz, 1H), 5.03 (s, 2H), 3.63 (s, 3H). Tr(METCR1410) = 0.72 min, m / z (ES) + [M+H] + = 210.1, 87%.

[0409] Step 2: Follow the same steps as in Step 4 of Method 9. Step 3: 3-(7,8-difluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)propanoic acid 7,8-Difluoro-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one (276 mg, 1.17 mmol), tetrabutylammonium bromide (189 mg, 0.59 mmol), ethyl acrylate (0.25 mL, 2.35 mmol), and KCO (162 mg, 1.17 mmol) were combined in THF (2 mL) and the reaction was heated to 80 °C for 4 h. The reaction was allowed to cool to room temperature and additional THF (2 mL) was added, followed by 2 M NaOH (0.59 mL, 1.17 mmol). The reaction was stirred vigorously at room temperature for 18 h. The volatiles were removed in vacuo and the aqueous phase was acidified using 2 M HCl. The resulting precipitate was filtered to yield the title compound. Tr(METCR1410) = 0.62 min, m / z (ES) + [M+H] + = 308.1, 68%.

[0410] Step 4: (3-{7,8-difluoro-1-methyl-4-oxo-1H,4H,5H-pyrazolo[4,3-c]quinolin-5-yl}-N-(2,4-difluorophenyl)propanamide 3-(7,8-Difluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)propanoic acid (357 mg, 1.16 mmol), 2,4-difluoroaniline (0.12 mL, 1.16 mmol), and DIPEA (0.61 mL, 3.49 mmol) were combined in DMF (17.62 mL), and T3P (50% in EtOAc) (0.85 mL, 1.74 mmol) was added. The reaction was stirred at room temperature for 18 hours. Additional 2,4-difluoroaniline (0.12 mL, 1.16 mmol), DIPEA (0.61 mL, 3.49 mmol), and 3-(7,8-difluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)propanoic acid (357 mg, 1.16 mmol) were added, and the reaction mixture was stirred at room temperature for another 3 h. Water was added to precipitate a solid, which was filtered. The precipitate was washed with water, EtOAc, and EtOH. Purification by basic preparative HPLC gave the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.29 (dd, J = 11.4, 8.6 Hz, 1H), 8.15 (s, 1H), 7.92 (dd, J = 13.6, 7.2 Hz, 1H), 7.80 (td, J = 9.0, 6.3 Hz, 1H), 7.34 - 7.24 (m, 1H), 7.11 - 7.01 (m, 1H), 4.57 (t, J = 7.3 Hz, 2H), 4.37 (s, 3H), 2.76 (t, J = 7.4 Hz, 2H). 19 F NMR (376 MHz, DMSO-d6) δ -112.17 - -116.63 (m), -117.81 - -121.79 (m), -133.63 (ddd, J = 22.5, 13.6, 8.6 Hz), -144.95 (ddd, J = 24.1, 11.3, 7.2 Hz). Tr(MET-uHPLC-AB-101) = 2.95 min, m / z (ES + )(M+H) + 419.2, 98%.

[0411] The following was also prepared by this route:

[0412] [Table 20]

[0413] Method 22 Method 22 scheme

[0414] [ka]

[0415] [Example 22-1] Step 1: N-(2,4-difluorophenyl)prop-2-enamide K2CO3 (4.28 mg, 31.0 mmol) was added to a solution of 2,4-difluoroaniline (1 g, 7.75 mmol) in acetone (30 mL) at room temperature under N2. Acryloyl chloride (1.9 mL, 23.2 mmol) was added dropwise over 5 minutes. The suspension was stirred at room temperature overnight, filtered, and concentrated to give a solid. The solid was triturated with heptane and dried in vacuo to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 9.95 (s, 1H), 7.97 - 7.88 (m, 1H), 7.33 (ddd, J = 11.6, 9.0, 2.9 Hz, 1H), 7.12 - 7.03 (m, 1H), 6.57 (dd, J = Tr(METCR1704) = 0.63 min, m / z (ES) + [M+H] + = 184.0, 99%.

[0416] Step 2: Follow the same steps as in Step 1 of Method 21. Step 3: Follow the same steps as in Step 4 of Method 9. Step 4: N-(2,4-difluorophenyl)-3-{7-fluoro-3-methyl-4-oxo-3H,4H,5H-pyrrolo[2,3-c]quinolin-5-yl}propanamide 7-Fluoro-3-methyl-5H-pyrrolo[2,3-c]quinolin-4-one (50 mg, 0.231 mmol), K2CO3 (45 mg, 0.324 mmol), and N-(2,4-difluorophenyl)prop-2-enamide (0.10 mL, 0.463 mmol) were combined in DMF (1 mL) in a pressure tube, and the reaction was heated to 80 °C for 3 h. After cooling to room temperature, DMSO (1.5 mL) was added, and the mixture was purified by high-pH preparative HPLC. The resulting residue was suspended in methanol (3 mL), heated, and sonicated until dissolution was nearly complete, then cooled to 4 °C for 1.5 h and filtered. The collected solid was dried in an oven to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.04 (dd, J = 8.7, 6.5 Hz, 1H), 7.81 (ddd, J = 9.0, 6.3 Hz, 1H), 7.49 (dd, J = 12.3, 2.2 Hz, 1H), 7.41 (d, J = 2.8 Hz, 1H), 7.30 (ddd, J = 11.7, 9.0, 2.9 Hz, 1H), 7.13 (ddd, J = 8.5, 2.3 Hz, 1H), 7.10 - 7.03 (m, 1H), 6.84 (d, J = 2.8 Hz, 1H), 4.63 - 4.45 (m, 2H), 4.09 (s, 3H), 2.82 - 2.71 (m, 2H). 19 F NMR (376 MHz, DMSO-d6) δ -113.55, -114.84, -119.54. Tr(MET-uHPLC-AB-101) = 3.46 min, m / z (ES + )(M+H) + 400, 100%.

[0417] Method 23 Method 23 scheme

[0418] [ka]

[0419] [Example 23-1] Step 1: 2,4-Difluoro-1,3-diiodo-5-nitro-benzene Periodic acid (312 mg, 1.37 mmol) was added to concentrated sulfuric acid (10 mL, 1.37 mmol), and the mixture was cooled to 0 °C before potassium iodide (681 mg, 4.10 mmol) was slowly added. After stirring for 15 minutes, 2,4-difluoro-1-nitrobenzene (0.15 mL, 1.37 mmol) was added dropwise, and the solution was stirred at 0 °C for 30 minutes. The reaction was warmed to 50 °C and stirred for 2 hours. The reaction was allowed to cool, then poured onto ice (50 mL) and extracted with TBME. The combined organics were washed with sodium thiosulfate solution (10%), dried over Na SO , filtered, and concentrated in vacuo. The crude residue was purified by column chromatography to provide the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 8.64 (dd, J = 8.3, 6.4 Hz, 1H). 19 F NMR (471 MHz, DMSO-d6) δ -62.38 (dd, J = 10.1, 6.0 Hz), -94.13 (d, J = 1.8 Hz).

[0420] Step 2: 2,4-Difluoro-3,5-diiodo-aniline 2,4-Difluoro-1,3-diiodo-5-nitro-benzene (200 mg, 0.487 mmol) was added to a solution of iron (109 mg, 1.95 mmol) in acetic acid (5 mL) and the reaction mixture was stirred at 80° C. for 1 h. The crude product mixture was cooled to room temperature, filtered, and washed with ethanol. The filtrate was concentrated in vacuo and the residue was partitioned between DCM and 1 M aqueous Na2CO3. The organic phase was dried (hydrophobic frit) and concentrated to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 7.19 (dd, J = 9.5, 6.5 Hz, 1H), 5.33 (s, 2H). Tr(METCR1410) = 1.25 min, m / z (ES + ) (M+H) + 381.7, 95%.

[0421] Step 3: 7-Fluoro-8-iodo-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one 7-Fluoro-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one (250 mg, 1.15 mmol), N-iodosuccinimide (388 mg, 1.73 mmol), and hydrogen tetrafluoroborate in water (50%, 0.72 mL, 5.76 mmol) were combined in acetonitrile (20 mL) in a pressure tube and stirred at 60 °C for 2 hours. The cooled reaction mixture was poured into saturated NaHCO solution (20 mL). The resulting precipitate was filtered, washed with 10% aqueous sodium thiosulfate solution (10 mL) and water (10 mL), and dried under vacuum at 40 °C overnight to yield the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.47 (d, J = 6.5 Hz, 1H), 8.09 (s, 1H), 7.27 (d, J = 9.3 Hz, 1H), 4.35 (s, 3H). Tr(METCR1410) = 1.07 min, m / z (ES + ) (M+H) + 343.9, 94%.

[0422] Steps 4-5: Follow steps 3-4 of Method 21. The following was prepared by this route:

[0423] [Table 21]

[0424] Method 24 Method 24 scheme

[0425] [ka]

[0426] [Example 24-1] Step 1: Follow the same steps as in Step 6 of Method 9. Step 2: 3-{7-fluoro-1-methyl-4-oxo-1H,4H,5H-pyrazolo[4,3-c]quinolin-5-yl}-N-[2-fluoro-4-(tributylstannyl)phenyl]propanamide A suspension of hexabutyldistannane (0.60 mL, 1.18 mmol) and N-(2-fluoro-4-iodo-phenyl)-3-(7-fluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)propanamide (300 mg, 0.590 mmol) in anhydrous toluene (30 mL) was degassed with N in a pressure tube for 5 minutes. Pd(PPh) (136 mg, 0.118 mmol) was added, the vial was sealed, and the reaction was stirred at 90 °C for 6 hours. The cooled reaction mixture was filtered through Celite (eluting with toluene). The filtrate was partitioned with brine, and the organic fraction was extracted with toluene. The combined organics were dried over NaSO, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.34 (dd, J = 9.0, 6.2 Hz, 1H), 8.13 (s, 1H), 7.87 - 7.79 (m, 1H), 7.65 (dd, J = 12.3, 2.5 Hz, 1H), 7.31 - 7.11 (m, 3H), 4.57 (t, J = 7.4 Hz, 2H), 4.36 (s, 3H), 2.78 (t, J = 7.5 Hz, 2H), 1.62 - 1.38 (m, 6H), 1.33 - 1.24 (m, 6H), 1.16 - 0.95 (m, 6H), 0.85 (t, J = 7.3 Hz, 9H). 19 F NMR (376 MHz, DMSO-d6) δ -108.66, -125.74. Tr(METCR1503) = 4.67 min, m / z (ES + ) (M+H) + 671.2, 673.2, 96%.

[0427] Step 3: N-(2,4-difluorophenyl)-3-(7-fluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)propanamide DMA (3 mL) was added to a vial containing 3-(7-fluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)-N-(2-fluoro-4-tributylstannyl-phenyl)propanamide (10 mg, 0.015 mmol), pyridine (0.018 mL, 0.223 mmol), copper(II) triflate (11 mg, 0.030 mmol), 18-crown-6 (2.0 mg, 7.45 μmol), and potassium fluoride (3.5 mg, 0.060 mmol) under nitrogen. The reaction mixture was stirred at 100° C. for 0.5 h. The reaction mixture was concentrated in vacuo and partitioned between DCM and water. The organic phase was extracted, dried (phase separator cartridge), and concentrated in vacuo. The resulting residue was dissolved in acetonitrile and methanol for purification by acidic-phase preparative HPLC to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.34 (dd, J = 9.0, 6.2 Hz, 1H), 8.14 (s, 1H), 7.80 (td, J = 9.0, 6.3 Hz, 1H), 7.65 (dd, J = 12.3, 2.3 Hz, 1H), 7.35 - 7.23 (m, 2H), 7.10 - 7.02 (m, 1H), 4.57 (t, J = 7.5 Hz, 2H), 4.36 (s, 3H), 2.76 (t, J = 7.4 Hz, 2H). Tr(MET-uHPLC-AB-101) = 2.81 min, m / z (ES + )(M+H) + 401.2, 98%.

[0428] Method 25 Method 25 scheme

[0429] [ka]

[0430] [Example 25-1] Step 1: 2-Fluoro-4-trimethylstannyl-aniline A suspension of hexamethyldistannane (8.29 g, 25.3 mmol) and 2-fluoro-4-iodoaniline (3.00 g, 12.7 mmol) in anhydrous 1,4-dioxane (75 mL) was degassed with N for 5 minutes. Pd(PPh3)4 (731 mg, 0.63 mmol) was added under nitrogen. The reaction was then stirred at 80 °C for 20 hours. The cooled reaction mixture was filtered, and DCM (25 mL) was added to the filtrate, which was then concentrated in vacuo onto silica. Purification by flash column chromatography and concentration of the fractions under a stream of nitrogen afforded the title compound. Tr(METCR1906) = 0.92 min, m / z (ES) + [M+H] + = 274.0, 275.9, 463.0, 89%.

[0431] Step 2: 3-(7-Fluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)-N-(2-fluoro-4-trimethylstannyl-phenyl)propanamide A solution of 3-(7-fluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)propanoic acid (300 mg, 1.04 mmol), 2-fluoro-4-trimethylstannyl-aniline (341 mg, 1.24 mmol), and EDC.HCl (298 mg, 1.56 mmol) in pyridine (9 mL) was stirred at room temperature for 3 hours. The solvent was removed in vacuo, and DCM and water were added. The organic phase was separated, dried (hydrophobic frit), and concentrated in vacuo. The crude residue was purified by flash column chromatography to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.34 (dd, J = 9.0, 6.3 Hz, 1H), 8.13 (s, 1H), 7.88 - 7.79 (m, 1H), 7.66 (dd, J = 12.2, 2.5 Hz, 1H), 7.39 - 7.15 (m, 3H), 4.57 (t, J = 7.5 Hz, 2H), 4.36 (s, 3H), 2.78 (t, J = 7.5 Hz, 2H), 0.27 (s, 9H). 19 F NMR (376 MHz, DMSO-d6) δ -108.67, -125.92. Tr(MET-CR-AB106) = 3.68 min, m / z (ES) + [M+H] + = 545.0, 546.9, 97%.

[0432] Step 3: N-(2,4-difluorophenyl)-3-(7-fluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)propanamide DMA (5 mL) was added to a vial containing 3-(7-fluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)-N-(2-fluoro-4-trimethylstannyl-phenyl)propanamide (20 mg, 0.032 mmol), pyridine (0.039 mL, 0.484 mmol), copper(II) triflate (23 mg, 0.065 mmol), 18-crown-6 (4.3 mg, 0.016 mmol), and potassium fluoride (7.5 mg, 0.129 mmol) under nitrogen, and the vessel was stirred at 100 °C for 3 h. The reaction mixture was concentrated in vacuo and partitioned between DCM and water. The organic phase was extracted, washed with water (x3), dried (phase separator cartridge), and concentrated in vacuo. The reaction was repeated on a 60 mg scale and the crude residues were combined and dissolved in acetonitrile and methanol for purification by acidic preparative HPLC to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.34 (dd, J = 8.9, 6.2 Hz, 1H), 8.13 (s, 1H), 7.89 - 7.76 (m, 1H), 7.65 (dd, J = 12.2, 2.3 Hz, 1H), 7.37 - 7.22 (m, 2H), 7.11 - 7.02 (m, 1H), 4.65 - 4.52 (m, 2H), 4.36 (s, 3H), 2.82 - 2.70 (m, 2H); m / z (ES) + [M+H] + = 401.1, 95%.

[0433] Method 26 Scheme of Method 26

[0434] [ka]

[0435] [Example 26-1] Step 1: 5-Bromo-2-(2-methylpyrazol-3-yl)aniline Divided into eight pressure vials: 5-Bromo-2-iodo-aniline (5.00 g, 16.8 mmol) was dissolved in 1,4-dioxane (160 mL). Water (16 mL), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (5.24 g, 25.2 mmol), and K2CO3 (6.96 g, 50.3 mmol) were added. The vial was degassed with N2 for 5 minutes, after which Pd(PPh3)4 (1.94 g, 1.68 mmol) was added, followed by degassing for an additional 5 minutes. The reaction mixture was stirred at 85 °C for 18 hours. The cooled combined reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ 7.50 (d, J = 1.8 Hz, 1H), 6.98 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 6.75 (dd, J = 8.1, 2.0 Hz, 1H), 6.27 (d, J = 1.8 Hz, 1H), 5.20 (s, 2H), 3.64 (s, 3H). Tr(METCR1704) = 0.79 min, m / z (ES + ) [M+H] + = 252.1, 254.1, 99%.

[0436] Step 2: 7-Bromo-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one CDI (4.01 g, 24.8 mmol) was added to a solution of 5-bromo-2-(2-methylpyrazol-3-yl)aniline (3.12 g, 12.4 mmol) in anhydrous NMP (40 mL), and the reaction mixture was stirred at 150° C. for 30 minutes under microwave irradiation. The reaction mixture was diluted with water (20 mL) and then stirred at 0° C. for 2 hours. The resulting precipitate was filtered under vacuum and washed with water to yield the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 11.50 (s, 1H), 8.14 (d, J = 8.7 Hz, 1H), 8.10 (s, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.46 (dd, J = 8.6, 2.0 Hz, 1H), 4.35 (s, 3H). Tr(METCR1704) = 0.64 min, m / z (ES + ) [M+H] + = 278.0, 280.0, 100%.

[0437] Step 3: 3-(7-bromo-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)propanoic acid A suspension of 7-bromo-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one (2.35 g, 8.45 mmol), K2CO3 (1.17 g, 8.45 mmol), tetrabutylammonium bromide (1.36 g, 4.23 mmol), and ethyl acrylate (1.8 mL, 16.9 mmol) was stirred neat at 80 °C for 3 h. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in THF (25 mL), then 2 M NaOH (13 mL, 25.4 mmol) was added, and the reaction was stirred at room temperature for 45 min. The reaction mixture was concentrated in vacuo to remove THF, acidified to pH 2-3 using 6 M aqueous HCl, and the resulting aqueous solution was extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Purification by trituration with EtOAc gave the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 8.22 (d, J = 8.6 Hz, 1H), 8.14 (s, 1H), 7.93 (d, J = 1.4 Hz, 1H), 7.57 (dd, J = 8.6, 1.5 Hz, 1H), 4.57 - 4.45 (m, 2H), 4.36 (s, 3H), 2.64 - 2.54 (m, 2H). Tr(METCR1704) = 0.65 min, m / z (ES + ) [M+H] + = 350.1, 352.1, 99%.

[0438] Step 4: 3-(7-bromo-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)-N-(2,4-difluorophenyl)propanamide HATU (1.50 g, 3.94 mmol), 3-(7-bromo-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)propanoic acid (920 mg, 2.63 mmol), 2,4-difluoroaniline (356 mg, 2.76 mmol), and DIPEA (1.4 mL, 7.88 mmol) were combined in DMF (25 mL) and the reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was concentrated in vacuo and partitioned between water and DCM. The organic fraction was separated and the aqueous phase was re-extracted with additional DCM. The combined organic extracts were washed with water and brine, dried (hydrophobic frit), and concentrated in vacuo. The crude residue was triturated with EtOH to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.22 (d, J = 8.7 Hz, 1H), 8.15 (s, 1H), 7.95 (d, J = 1.5 Hz, 1H), 7.80 (ddd, J = 9.1, 6.4 Hz, 1H), 7.56 (dd, J = 8.6, 1.7 Hz, 1H), 7.29 (ddd, J = 11.7, 9.0, 2.9 Hz, 1H), 7.11 - 7.01 (m, 1H), 4.59 (t, J = 7.2 Hz, 2H), 4.36 (s, 3H), 2.76 (t, J = 7.2 Hz, 2H). Tr(METCR1704) = 0.82 min, m / z (ES) + [M+H] + = 461.0, 463.0, 92%.

[0439] Step 5: N-(2,4-difluorophenyl)-3-[1-methyl-4-oxo-7-(trimethylstannyl)-1H,4H,5H-pyrazolo[4,3-c]quinolin-5-yl]propanamide A suspension of hexamethyldistannane (355 mg, 1.08 mmol) and 3-(7-bromo-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)-N-(2,4-difluorophenyl)propanamide (250 mg, 0.54 mmol) in anhydrous toluene (25 mL) was sonicated and degassed with N in a pressure tube for 5 minutes before adding Pd(PPh) (125 mg, 0.108 mmol) under nitrogen. The reaction vessel was sealed and stirred at 90 °C for 2.5 hours. The cooled reaction mixture was filtered through Celite and washed with additional toluene. The filtrate was partitioned with brine and the organic fraction was separated. The combined organics were dried over NaSO, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.30 - 8.19 (m, 1H), 8.13 (s, 1H), 7.84 - 7.67 (m, 2H), 7.49 (d, J = 7.7 Hz, 1H), 7.28 (ddd, J = 11.1, 9.0, 2.9 Hz, 1H), 7.06 - 7.02 (m, 1H), 4.63 (t, J = 7.2 Hz, 2H), 4.37 (s, 3H), 2.77 (t, J = 7.2 Hz, 2H), 0.32 (s, 9H). 19 F NMR (376 MHz, DMSO-d6) δ -114.80 (d, J = 5.3 Hz), -119.42 (d, J = 5.3 Hz). Tr(MET-uHPLC-AB-101) = 3.88 min, m / z (ES + )(M+H) + 545.0, 546.9, 100%.

[0440] Step 6: N-(2,4-difluorophenyl)-3-(7-fluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)propanamide DMA (4 mL) was added to a vial containing N-(2,4-difluorophenyl)-3-(1-methyl-4-oxo-7-trimethylstannyl-pyrazolo[4,3-c]quinolin-5-yl)propanamide (20 mg, 0.037 mmol), pyridine (0.044 mL, 0.550 mmol), copper(II) triflate (27 mg, 0.074 mmol), 18-crown-6 (4.8 mg, 0.018 mmol), and potassium fluoride (8.5 mg, 0.147 mmol) under nitrogen. The reaction mixture was stirred at 100 °C for 1.5 h. The product was observed in the LCMS trace by comparison of the retention time with a reference sample. Tr(MET-uHPLC-AB-101) = 2.82 min, m / z (ES + )(M+Na) + 423.1, 10%.

[0441] Method 27 Scheme of Method 27

[0442] [ka]

[0443] [Example 27-1] Step 1: [3-Fluoro-4-[3-(7-fluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)propanoylamino]phenyl]boronic acid DIPEA (1.0 mL, 5.70 mmol) was added to a solution of T3P (50% in EtOAc, 1.4 mL, 2.85 mmol), 3-(7-fluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)propanoic acid (550 mg, 1.90 mmol), and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (451 mg, 1.90 mmol) in DMF (25 mL). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated in vacuo and triturated with water. Further purification by trituration from acetonitrile (4 mL) gave the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.34 (dd, J = 9.0, 6.3 Hz, 1H), 8.13 (d, J = 1.7 Hz, 1H), 7.92 (t, J = 7.8 Hz, 1H), 7.66 (dd, J = 12.2, 2.2 Hz, 1H), 7.60 - 7.50 (m, 2H), 7.27 (td, J = 8.8, 2.4 Hz, 1H), 4.65 - 4.53 (m, 2H), 4.36 (s, 3H), 2.80 (t, J = 7.3 Hz, 2H).Tr(METCR1410) = 1.00min, (ES) + [M+H] + = 427.0, 77%.

[0444] Step 2: [3-fluoro-4-[3-(7-fluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)propanoylamino]phenyl]-(2,4,6-trimethylphenyl)iodonium tetrafluoroborate A solution of finely ground [3-fluoro-4-[3-(7-fluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)propanoylamino]phenyl]boronic acid (77%, 154 mg, 0.361 mmol) in anhydrous DCM (100 mL) was sonicated under nitrogen until a fine suspension was achieved. The suspension was cooled to 0 °C, and boron trifluoride diethyl etherate (0.13 mL, 1.08 mmol) was added. The reaction mixture was stirred for 10 minutes. A solution of iodomesitylene diacetate (145 mg, 0.397 mmol) in DCM (3 mL) was added at 0 °C. The reaction was allowed to warm to room temperature and stirred for 1.5 hours. The reaction mixture was re-treated with a solution of iodomesitylene diacetate (145 mg, 0.397 mmol) in DCM (3 mL) at 0 °C and stirred overnight at room temperature. After 22 h, the reaction mixture was re-treated with a solution of iodomesitylene diacetate (145 mg, 0.397 mmol) in DCM (3 mL) at 0 °C, sonicated, and stirred for an additional 24 h. The reaction mixture was cooled to 0 °C, treated with boron trifluoride diethyl etherate (0.13 mL, 1.08 mmol), stirred for 10 min, and then iodomesitylene diacetate (145 mg, 0.397 mmol) in DCM (3 mL) was added. The reaction was allowed to warm to room temperature and stirred overnight. A saturated solution of NaBF (50 mL) was added to the reaction mixture. The mixture was stirred for 10 min and then filtered. The precipitate was discarded (a mixture of starting material and product). The layers of the filtrate were separated and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude product was triturated with DCM (2 x 3 mL) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.34 (dd, J = 9.0, 6.3 Hz, 1H), 8.17 - 8.09 (m, 2H), 8.04 (dd, J = 9.8, 2.0 Hz, 1H), 7.85 - 7.75 (m, 1H), 7.63 (dd, J = 12.2, 2.4 Hz, 1H), 7.30 - 7.19 (m, 3H), 4.57 (t, J = 7.2 Hz, 2H), 4.36 (s, 3H), 2.82 (t, J = 7.2 Hz, 2H), 2.62 (s, 6H), 2.31 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -108.71, -119.89, -148.25, -148.31. Tr(MET-uHPLC-AB-101) = 2.00 min, m / z (ES + ) (M+H) + 627.2, 97%.

[0445] Step 3: N-(2,4-difluorophenyl)-3-(7-fluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)propanamide A mixture of copper(II) triflate (2.5 mg, 7.00 μmol), 18-crown-6 (3.7 mg, 0.014 mmol), [3-fluoro-4-[3-(7-fluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)propanoylamino]phenyl]-(2,4,6-trimethylphenyl)iodonium; tetrafluoroborate (5.0 mg, 7.00 μmol), and potassium fluoride (0.61 mg, 0.0105 mmol) in anhydrous DMF (1 mL, degassed with N for 5 minutes before reaction) was stirred under N in a pressure vial at 85° C. for 30 minutes. The reaction was quenched with water (1 mL) and concentrated in vacuo. The residue was purified by acidic preparative HPLC to provide the title compound. Tr(MET-uHPLC-AB-101) = 2.81 min, m / z (ES + ) (M+H) + 401.1, 93%.

[0446] Method 28 Method 28 scheme

[0447] [ka]

[0448] [Example 28-1] Step 1: 1,2-Dibenzyloxy-4-bromo-5-nitro-benzene 1,2-Dibenzyloxy-4-bromo-benzene (1.00 g, 2.71 mmol) was suspended in acetic acid (15 mL) and the mixture was warmed to 50 °C until it went into solution. The solution was then allowed to cool to room temperature and nitric acid (70%, 0.78 mL, 12.2 mmol) was added slowly dropwise. The reaction was stirred at room temperature for 20 hours, by which time a solid had precipitated. The mixture was carefully poured onto ice and the precipitate was then filtered. The solid was dissolved in DCM and washed with saturated aqueous NaHCO3 until the aqueous phase remained basic. The organics were dried (hydrophobic frit) and concentrated in vacuo to give the title compound. 1 H NMR (500 MHz, CDCl3) δ 7.63 (s, 1H), 7.45 - 7.31 (m, 10H), 7.19 (s, 1H), 5.21 (s, 2H), 5.18 (s, 2H). Tr(METCR1704) = 1.13 min, m / z (ES) + [M+H] + = No mass ions observed, 96%.

[0449] Step 2: Follow the same steps as in Step 1 of Method 21. Step 3: 4,5-Dibenzyloxy-2-(2-methylpyrazol-3-yl)aniline Ammonium chloride (722 mg, 13.5 mmol) was added to a suspension of 5-(4,5-dibenzyloxy-2-nitro-phenyl)-1-methyl-pyrazole (676 mg, 1.63 mmol) in a mixture of water (4 mL) and ethanol (6 mL), followed by the portionwise addition of iron powder (454 mg, 8.14 mmol). The reaction was then stirred at 70° C. for 75 minutes, allowed to cool, filtered through Celite, and washed with EtOAc. The filtrate was washed with brine. The organic layer was dried over NaSO, filtered, and concentrated in vacuo to provide the title compound. 1 H NMR (500 MHz, CDCl3) δ 7.51 (d, J = 1.8 Hz, 1H), 7.49 - 7.45 (m, 2H), 7.42 - 7.36 (m, 4H), 7.36 - 7.27 (m, 4H), 6.65 (s, 1H), 6.44 (s, 1H), 6.24 (d, J = 1.9 Hz, 1H), 5.17 (s, 2H), 5.07 (s, 2H), 3.59 (s, 3H). Tr(METCR1704) = 0.94 min, m / z (ES) + [M+H] + = 386.2, 94%.

[0450] Step 4: 7,8-Dibenzyloxy-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one 4,5-Dibenzyloxy-2-(2-methylpyrazol-3-yl)aniline (0.30 mL, 1.64 mmol) was dissolved in anhydrous DMF (10 mL) and CDI (796 mg, 4.91 mmol) was added. The mixture was heated to 120° C. under microwave irradiation for 20 minutes. The reaction mixture was carefully poured onto water. The precipitate was collected by filtration and washed with additional water to produce the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 7.99 (s, 1H), 7.64 (s, 1H), 7.49 (t, J = 6.8 Hz, 2H), 7.46 - 7.27 (m, 8H), 7.16 (s, 1H), 5.27 (s, 2H), 5.20 (s, 2H), 4.26 (s, 3H). Tr(METCR1704) = 0.88 min, m / z (ES) + [M+H] + = 412.3, 74%.

[0451] Step 5: Follow the same steps as in Step 3 of Method 21. Step 6: 3-(7,8-Dibenzyloxy-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)-N-(2,4-difluorophenyl)propanamide 3-(7,8-Dibenzyloxy-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)propanoic acid (84 mg, 0.17 mmol) was dissolved in pyridine (6.3 mL) and 2,4-difluoroaniline (0.02 mL, 0.21 mmol) was added, followed by EDC.HCl (50 mg, 0.26 mmol). The mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. Water and a small amount of EtOAc were added and the resulting precipitate was filtered. The solid was washed with more EtOAc and the organic phase from the filtrate was separated from the aqueous phase, dried (hydrophobic frit) and concentrated in vacuo to provide the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.05 (s, 1H), 7.85 - 7.75 (m, 1H), 7.71 (s, 1H), 7.49 (t, J = 7.0 Hz, 4H), 7.44 - 7.36 (m, 4H), 7.36 - 7.25 (m, 4H), 7.06 (t, J = 9.2 Hz, 1H), 5.32 (s, 4H), 4.55 (t, J = 7.2 Hz, 2H), 4.27 (s, 3H), 2.71 - 2.66 (m, 2H). Tr(METCR1704) = 1.02 min, m / z (ES)+ [M+H] + = 595.1, 92%.

[0452] Step 7: 2,4-difluorophenyl)-3-{7,8-dihydroxy-1-methyl-4-oxo-1H,4H,5H-pyrazolo[4,3-c]quinolin-5-yl}propanamide 3-(7,8-Dibenzyloxy-1-methyl-4-oxo-pyrazolo[4,3-c]quinolin-5-yl)-N-(2,4-difluorophenyl)propanamide (52 mg, 0.0875 mmol) was dissolved in ethanol (6 mL) and EtOAc (6 mL) under a N atmosphere, and Pd(OH) (5.0%, 37 mg, 0.01 mmol) was added. The reaction mixture was stirred under a hydrogen atmosphere (balloon) at room temperature for 18 hours. The reaction mixture was filtered through Celite and washed with EtOAc, ethanol, and DCM. The filtrate was concentrated in vacuo and purified by column chromatography to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.00 (s, 1H), 7.89 - 7.78 (m, 1H), 7.62 (s, 1H), 7.31 (ddd, J = 11.7, 9.1, 2.9 Hz, 1H), 7.16 - 7.02 (m, 2H), 4.51 - 4.40 (m, 2H), 4.27 (s, 3H), 2.79 - 2.69 (m, 2H). 19 F NMR (376 MHz, DMSO-d6) δ -114.77 (d, J = 5.1 Hz), -119.34 (d, J = 5.1 Hz). Tr(MET-uHPLC-AB-101) = 2.08 min, m / z (ES + )(M+H) + 415.2, 100%.

[0453] Biological assays Exon1-Q46 radioligand binding assay For radioligand binding assays (RBA), MBP-HTT(1-89)Q46-His(6x) ("Exon1-Q46") protein was prepared based on a previous publication (Scherzinger et al., Cell, Vol. 90, pp. 549-558, August 8, 1997). For the experiment, 30 μM MBP-Exon1-Q46 was incubated with 150 μg / mL thrombin and 2 mM CaCl2 in assay buffer (150 mM NaCl, 50 mM Tris, pH 8.0) at 37°C for 16 h. Aggregated Exon1-Q46 was pelleted by centrifugation at 13,000 rpm for 5 min in a tabletop centrifuge and redissolved in an equal volume of assay buffer. Test compounds were prepared at 11 concentrations ranging from 63 μM to 2 nM by titration in DMSO. For RBA, Q46 protein aggregates and test compounds were pre-incubated in assay buffer at 100 μL / well in a 96-well plate (pp, round bottom) for 20 min at room temperature. Ligand was then added at 50 μL / well and incubated at 37°C for 60 min. Final assay concentrations were 1 μM to 30 pM test compound, 1 μM Exon1-Q46 protein (equivalent monomer concentration), and 0.3 nM ligand [ 3 The antibody was [H3-methyl]-5-((5-methoxypyridin-2-yl)methoxy)-2-(pyrazin-2-yl)benzo[d]oxazole. Samples were transferred onto GF / B filter plates and washed twice with PBS (200 μL) using a Filtermate harvester. After drying the filter plates at 55°C for 1 hour, the plates were sealed under foil and 30 μL / well of scintillation fluid (Packard MicroScint 40) was added, incubated for 15 minutes in the dark, and counted on a MicroBeta reader. For analysis, replicate data from independent assay plates were compared against vehicle control wells (0% inhibition) and 1 μM unlabeled [ 3 IC was normalized to 0% inhibition and 100% inhibition using [H3-methyl]-5-((5-methoxypyridin-2-yl)methoxy)-2-(pyrazin-2-yl)benzo[d]oxazole (100% inhibition). 50Values ​​were calculated using normalized replicate data and four variables (top, bottom, slope, IC) in the overall fit. 50 ) was determined using the S-order inhibition model.

[0454] The results for various example compounds were as provided in the table below (+++<100 nM; ++100-500; +500-10000; ND: Not determined):

[0455] [Table 22] TIFF0007796054000149.tif239141TIFF0007796054000150.tif83142

[0456] PET imaging example The following example illustrates an exemplary, non-limiting procedure that may be utilized when conducting a PET imaging study on an individual in a clinical setting. The individual is naive or previously dosed with an unlabeled compound. The individual may fast prior to PET imaging and is allowed free access to water. A 20G, 2-inch intravenous catheter is inserted into the contralateral ulnar vein for administration of the imaging agent.

[0457] A human subject is placed in the PET camera and a tracer dose of imaging agent is administered via an intravenous catheter. Arterial or venous blood samples are obtained at appropriate time intervals during the PET scan to analyze and quantify the fraction of unmetabolized compound in the plasma. Images are acquired over a maximum period of 120 minutes. Within 10 minutes of the injection of the radiotracer, and at the end of the imaging session, 1 ml blood samples are obtained to determine the plasma concentration of any unlabeled imaging agent (or other interventional compound) that may have been administered prior to the PET tracer.

[0458] Tomographic images are obtained by image reconstruction. Regions of interest (ROIs) are established on the reconstructed images, for example, to determine the distribution of the imaging agent. Regions of interest in brain images may include, for example, the striatum, cerebellum, or basal ganglia. The amount of imaging agent absorbed 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).

[0459] 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.

[0460] The disclosure illustratively described herein can suitably be practiced without any element or elements, or limitation or limitations, not specifically disclosed herein. Thus, for example, terms such as "comprising," "including," and "containing" should be interpreted openly and without limitation. Furthermore, the terms and expressions used herein are used as terms of description rather than limitation, and the use of such terms and expressions is not intended to exclude equivalents of the features shown and described or portions thereof, but recognizes that various modifications are possible within the scope of the present disclosure.

[0461] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, as if each were individually incorporated by reference. In case of conflict, the present specification, including definitions, will control. The following is one embodiment of the present invention. (1) Formula I: [ka] [A 1 is C; A 2 is C or N; A 3 is CR 21 , N.R. 3 , or N; A 4 is CR 22 , N.R. 3 , or N; A 5 is 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 C3~6 is cycloalkyl; Each R 3 are independently hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, or C 3~6 is cycloalkyl; A 6 is CR 11 Or N and A 7 is CR 12 Or N and A 8 is CR 13 Or N and A 9 is CR 14 Or N and A 6 、A 7 、A 8 , and A 9 Not 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 and 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 may be linked together with any intervening atoms to form a 3- to 6-membered ring; L 1 is 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, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein the compound is labeled with one or more radioactive isotopes. (2) Formula I:

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Claims

1. Formula I: 【Chemistry 1】 [A 1 is C; A 2 is C or N; A 3 is CR 21 , N.R. 3 , or N; A 4 is CR 22 , N.R. 3 , or N; A 5 is 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 is CR 11 Or N and A 7 is CR 12 Or N and A 8 is CR 13 Or N and A 9 is CR 14 Or N and A 6 , A 7 , A 8 , and A 9 Not 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 and 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 joins together with any intervening atoms to form a 3- to 6-membered ring; L 1 is 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 a pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein the compound is labeled with one or more radioactive isotopes.

2. Formula Ia: 【Chemistry 2】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of stereoisomers thereof.

3. Formula IIa: 【Transformation 3】 [R b Ha-L 2 -X 1 and R a is as defined in claim 1; or R a and R b is one to four R with optional intervening atoms. 4 forming a 3- to 10-membered heterocyclyl ring optionally substituted by or a pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of stereoisomers thereof.

4. Formula IIb: 【Chemistry 4】 [R b Ha-L 2 -X 1 and R a is as defined in claim 1; or R a and R b is one to four R with optional intervening atoms. 4 forming a 3- to 10-membered heterocyclyl ring optionally substituted by or a pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of stereoisomers thereof.

5. Formula IIc: 【Transformation 5】 [R b Ha-L 2 -X 1 and R a is as defined in claim 1; or R a and R b is one to four R with optional intervening atoms. 4 forming a 3- to 10-membered heterocyclyl ring optionally substituted by or a pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of stereoisomers thereof.

6. Formula IId: 【Transformation 6】 [R b Ha-L 2 -X 1 and R a is as defined in claim 1; or R a and R b is one to four R with optional intervening atoms. 4 forming a 3- to 10-membered heterocyclyl ring optionally substituted by or a pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of stereoisomers thereof.

7. R 11 , R 12 , R 13 , or R 14 The compound of any one of claims 1 to 6, wherein one of is halo.

8. R 11 , R 12 , R 13 , or R 14 The compound of any one of claims 1 to 6, wherein one of is fluoro.

9. R 13 The compound of any one of claims 1 to 6, wherein is halo.

10. R 13 The compound of any one of claims 1 to 6, wherein is fluoro.

11. R 11 , R 12 , R 13 , or R 14 One of them is C 1～4 The compound of any one of claims 1 to 6, which is alkoxy.

12. R 11 , R 12 , R 13 , or R 14 The compound of any one of claims 1 to 6, wherein one of is methoxy.

13. R 13 The compound of any one of claims 1 to 6, wherein is methoxy.

14. R 21 , R 22 , and R 23 The compound of any one of claims 1 to 6, wherein one of is methyl.

15. R 21 , R 22 , and R 23 The compound of any one of claims 1 to 6, wherein one of is halo.

16. R 3 The compound of any one of claims 1 to 6, wherein is methyl.

17. X 1 C 6～10 The compound of any one of claims 1 to 6, which is aryl.

18. X 1 The compound of any one of claims 1 to 6, wherein is phenyl.

19. X 1 The compound of any one of claims 1 to 6, wherein is heteroaryl.

20. X 1 20. The compound of claim 19, wherein is pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl.

21. X 1 The compound of any one of claims 1 to 6, wherein is heterocyclyl.

22. X 1 22. The compound of claim 21, wherein is 1-piperidinyl, 4-morpholinyl, piperazin-1-yl, piperazin-3-one-1-yl, pyrrolidin-1-yl, or pyridazin-3(2H)-one-6-yl.

23. R 4 Halo, hydroxy, C 1～4 Alkyl, C 1～4 Haloalkyl, or C 1～4 The compound of any one of claims 1 to 6, which is alkoxy.

24. R 4 The compound of any one of claims 1 to 6, wherein is halo.

25. R 4 25. The compound of claim 24, wherein is fluoro.

26. X 1 is phenyl and R 4 25. The compound of claim 24, wherein is fluoro.

27. X 1 is phenyl and R 4 Halo, hydroxy, C 1～4 Alkyl, C 1～4 Haloalkyl, or C 1～4 The compound of any one of claims 1 to 6, which is alkoxy.

28. X 1 28. The compound of claim 27, wherein is 2-fluorophenyl.

29. X 1 28. The compound of claim 27, wherein is 2,4-difluorophenyl.

30. X 1 28. The compound of claim 27, wherein is 2,5-difluorophenyl.

31. R a and R b may contain one to four R 4 The compound according to any one of claims 3 to 6, which forms a 3-10 membered heterocyclyl ring optionally substituted by:

32. The compound of any one of claims 1 to 6, wherein m is 2.

33. The compound of any one of claims 1 to 6, wherein m is 3.

34. L 2 7. The compound of claim 1, wherein:

35. Each R 6 The compound of any one of claims 1 to 6, wherein is hydrogen.

36. A 6 is CR 11 and A 7 is CR 12 and A 8 is CR 13 and A 9 is CR 14 The compound according to any one of claims 1 to 6, wherein

37. A 6 , A 7 , A 8 , and A 9 One of the is N and the rest is CR, if applicable. 11 , C.R. 12 , C.R. 13 , or CR 14 The compound according to any one of claims 1 to 6, wherein

38. R 11 , R 12 , R 13 , and R 14 7. The compound of any one of claims 1 to 6, wherein each of is hydrogen. 【Request Item 39】 【Table 1】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein the compound is: 【Request Item 40】 【Table 2】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein the compound is:

41. 11 C. 13 N, 15 O, and 18 41. The compound of any one of claims 1, 39, or 40, containing one or more positron-emitting radioisotopes selected from F.

42. 42. An imaging agent comprising a compound according to any one of claims 39 to 41, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of stereoisomers thereof.

43. An imaging agent comprising a compound according to any one of claims 1 or 39 to 41 or the imaging agent according to claim 42 for use in a method for producing a diagnostic image in an individual, the method comprising administering an effective amount of the imaging agent to the individual and producing an image of a body part or region of the individual.

44. 44. The imaging agent of claim 43, wherein generating an image of a body part or body region of an individual comprises generating an image to detect the presence or absence of aggregation-prone proteins in the image.

45. 45. The imaging agent of claim 44, wherein the aggregation-prone protein is huntingtin protein (HTT protein).

46. 46. ​​The imaging agent of claim 45, wherein the HTT protein is found in the basal ganglia.

47. 46. ​​The imaging agent of claim 44 or 45, wherein the presence or absence of protein aggregates corresponds to the presence or absence of a neurodegenerative disease.

48. 48. The imaging agent of claim 47, wherein the neurodegenerative disease is selected from Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, prion diseases, and spinocerebellar ataxias.

49. 49. The imaging agent of claim 48, wherein the neurodegenerative disease is Huntington's disease (HD).

50. 50. The imaging agent of claim 49, wherein the effective amount of the imaging agent comprises 0.1 to 20 mCi.

51. 51. The imaging agent of claim 50, wherein the effective amount of the imaging agent comprises 10 mCi.

52. 50. The imaging agent of claim 49, 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.

53. 53. The imaging agent of claim 52, wherein generating an image comprises PET imaging.

54. 46. ​​The imaging agent of claim 45, wherein the HTT protein is present as an oligomer or aggregate, or a combination thereof.

55. 46. ​​The imaging agent of claim 45, wherein the HTT protein is a mutant.

56. 44. The imaging agent of claim 43, wherein the body part or body region is the head, spinal cord, limb, chest or abdomen.

57. 44. The imaging agent of claim 43, wherein the body part or body region is the brain.

Images