Heterocyclic compounds and imaging agents for imaging huntingtin protein

Abstract

This invention provides specific compounds and imaging agents, compositions thereof, and methods of using them, which are useful for detecting diseases or conditions related to protein aggregation, particularly huntingtin protein aggregation. [Solution] Formula I: TIFF2026053514000158.tif35147 The provided material includes compounds labeled with one or more radioactive isotopes, or isotope-enriched analogs thereof, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers.

Description

[Technical Field]

[0001] Cross-reference of 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] Compounds and imaging agents, compositions thereof, and methods of using them are provided herein, which are useful for detecting, treating, or preventing diseases or conditions related to protein aggregation. [Background technology]

[0003] The emergence 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, both before symptom onset and in the clinical environment. Such measurements are rapidly expanding their diagnostic applications, their use in evaluating treatment responses, and their role in supporting drug development. The introduction of high-resolution molecular imaging techniques is seen by many experts as a major breakthrough.

[0004] PET involves administering a positron-emitting radionuclide tracer to a target and subsequently detecting positron emission (annihilation) events within the body. Radionuclide tracers typically consist of target molecules that incorporate one or more positron-emitting radionuclides.

[0005] Molecular probes labeled with positron-emitting radionuclides and related PET imaging assays are under development for targeting, detecting, visualizing, and quantifying various extracellular and intracellular molecules as well as 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 spreading to other subcortical brain regions. HD is caused by an elongated CAG triplet repeat in the exon-1 region of the huntingtin gene (HTT). The resulting polyglutamate domain elongation induces misfolding and conformational changes in the mutant huntingtin (mHTT) protein, potentially leading to the formation of protein aggregates. HD has a global incidence of 5–10 cases per 100,000 people, making it the most common hereditary, monogenic neurodegenerative disorder.

[0007] As with any medical condition, treatment for hemorrhagic disease (HD) should ideally be initiated at or before the onset of early signs of the disease. Therefore, reliable early indicators of disease onset and pharmacodynamic biomarkers of disease progression are highly desirable. [Overview of the Initiative] [Problems that the invention aims to solve]

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

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

[0010] Some embodiments provide compounds of formula I' 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 18It contains one or more positron-emitting radioisotopes selected from F. In some embodiments, there is provided an imaging agent comprising a compound of formula I', or an isotope-enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers.

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

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

[0013] There is also provided an imaging agent comprising a compound as described herein, wherein the compound is labeled with one or more positron-emitting radionuclides. In some embodiments, the compound 11 C, 13 N, 15 O, and 18 contains one or more positron-emitting radionuclides selected from F.

[0014] There is also provided a method for generating a diagnostic image, such as a positron emission tomography (PET) image, in an individual, comprising administering an effective amount of a compound as described herein or an imaging agent comprising a compound as described herein, and generating an image of a body part or body region of the individual.

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

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

[0017] In some embodiments, compounds or imaging agents for use as described herein are provided, wherein the presence or absence of protein aggregates corresponds to the presence or absence of neurodegenerative disease.

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

[0019] In some embodiments, compounds or imaging agents for use as described herein are provided, wherein the effective amount of the imaging agent is about 0.1 to about 20 mCi. In some embodiments, compounds or imaging agents for use as described herein are provided, wherein the effective amount of the imaging agent is about 10 mCi.

[0020] In some embodiments, compounds or imaging agents for use as described herein are provided, wherein generating an image includes positron emission tomography (PET) imaging, PET with simultaneous computed tomography (PET / CT), PET with simultaneous magnetic resonance imaging (PET / MRI), single-photon emission computed tomography (SPECT) imaging, or a combination thereof. In some embodiments, compounds or imaging agents for use as described herein are provided, wherein generating an image includes PET imaging.

[0021] In some embodiments, compounds or imaging agents for use as described herein are provided, wherein the HTT protein exists as an oligomer or aggregate, or a combination thereof. In some embodiments, compounds or imaging agents for use as described herein are provided, wherein the HTT protein is a variant.

[0022] In some embodiments, compounds or imaging agents for use as described herein are provided, wherein the body part or region is the head, spinal cord, limb, chest, or abdomen. In some embodiments, compounds or imaging agents for use as described herein are provided, wherein the body part or region is the brain. [Modes for carrying out the invention]

[0023] The following description provides exemplary embodiments of the present technology. However, it should be recognized that such descriptions are not intended to limit the scope of the present invention, but rather are provided as exemplary embodiments.

[0024] definition In this specification, the following words, phrases, and symbols are intended to have the meanings set forth below, except to the extent that the context in which they are used indicates otherwise.

[0025] The compounds described herein refer to any compound of any formula described herein, including the compounds of formula I', formula I, formula Ia, formula IIa, formula IIb, formula IIc, and formula IId, or their isotopically labeled analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers, or any compound described anywhere in this specification, including the examples, or the compounds of Table 1A or Table 1B, or labeled isomers of such compounds as defined in the specification, or imaging agents or pharmaceutical compositions containing such compounds or labeled compounds.

[0026] A dash ("-") that is not between two letters or two symbols is used to indicate a bond point to the parent structure for a substituent. For example, -C(O)NH2 is bonded to the parent structure through a carbon atom. Dashes preceding or at the end of a chemical group are for convenience; chemical groups can be illustrated with or without one or more dashes without losing their usual meaning. Dashed or dashed lines drawn through bonds in a structure indicate specific bond points. 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 This indicates that, excluding further substitutions, the following groups have u to v carbon atoms. For example, "C 1~6 "Alkyl" refers to an alkyl group consisting of 1 to 6 carbon atoms.

[0028] In this specification, references to a “approximate” value or parameter include (and describe) embodiments relating to that value or parameter itself. In certain embodiments, the term “approximately” includes ±10% of the indicated amount. In other embodiments, the term “approximately” includes ±5% of the indicated amount. In certain other embodiments, the term “approximately” includes ±1% of the indicated amount. Also, the term “approximately X” includes the description of “X.” Furthermore, the singular forms “a” and “the” include multiple references unless the context explicitly indicates otherwise. Thus, for example, a reference to “the compound” includes multiple such compounds, and a reference to “the assay” includes one or more assays and their equivalents known to those skilled in the art.

[0029] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to a chain with 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 1~4Alkyl compounds include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbon atoms is named by its chemical name or specified by its molecular formula, all positional isomers having that number of carbon atoms may be included. 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] Instead of the terms provided herein, alternative chemical names known to those skilled in the art may be used. For example, divalent groups, such as divalent "alkyl" groups and divalent "aryl" groups, may also be called "alkylene" or "arylene" groups, respectively. Furthermore, unless otherwise expressly indicated, when a combination of groups is referred herein as a single part, for example, as arylalkyl or aralkyl, the last group described contains the atom to which that part is bonded to the rest of the molecule.

[0031] "Alkenyl" contains at least one carbon-carbon double bond and 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 2-4 carbon atoms (i.e., C 2~4 This refers to an alkyl group having an alkenyl group. Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl), and isoprenyl.

[0032] "Alkynyl" contains at least one carbon-carbon triple bond and 2 to 20 carbon atoms (i.e., C 2~20 Alkynyl), 2 to 8 carbon atoms (i.e., C 2~8 Alkynyl), 2-6 carbon atoms (i.e., C 2~6 Alkynyl) or 2-4 carbon atoms (i.e., C 2~4 This refers to an alkyl group having an alkynyl bond. The term "alkynyl" also includes groups having one triple bond and one double bond.

[0033] "Alkoxy" refers to the "alkyl-O-" group. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0034] "Alkylamino" refers to the "alkyl-NH-" group. Examples of alkylamino groups include methylamino, ethylamino, isopropylamino, tert-butylamino, and n-hexylamino. "Dialkylamino" refers to the "(alkyl)2N-" group. Examples of dialkylamino groups include dimethylamino, diethylamino, (isopropyl)(methyl)amino, (n-pentyl)(tert-butyl)amino, and di-n-hexylamino.

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

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

[0037] "Amide" is -C(O)NR y R z The group referred to is the "C-amide" group, and -NR y C(O)R z The "N-amide" group refers to the group (in the formula, R y and R z These are independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl, each of which may be optionally substituted as defined herein, or R y and R z Together, these form a cycloalkyl or heterocycline, 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 '' independently refers to hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. In some embodiments, 'amino refers to an NH2 group.

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

[0040] "Aryl" refers to an aromatic carbocyclic group having a monocyclic (e.g., monocyclic) or polycyclic (e.g., bicyclic or tricyclic) system including a condensed system. As used herein, aryl refers to a ring carbon atom (i.e., C) with 6 to 20 carbon atoms. 6~20 aryl) or 6 to 10 carbon ring atoms (i.e., C 6~10 It contains an aryl group. Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. However, aryl never includes or overlaps with heteroaryls 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 "aryl-alkyl-" group.

[0042] "Carbamoyl" is -OC(O)NR y R z The group referred to is the "O-carbamoyl" group and -NR y C(O)OR z The "N-carbamoyl" group (in the formula, R) refers to the group y and R z This refers independently to both hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl, each of which may be substituted as provided herein.

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

[0044] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having monocyclic or polycyclic structures including condensed, crosslinked, and spirocyclic systems. The term "cycloalkyl" refers to a cycloalkenyl group (i.e., a cyclic group having at least one double bond) and at least one sp 3 It comprises a carbocyclic fused ring system having ring carbon atoms (i.e., at least one non-aromatic ring). As used herein, cycloalkyl has 3 to 20 ring carbon atoms (i.e., C 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 a ring of 3-6 carbon atoms (i.e., C 3~6 It has a cycloalkyl group. 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, norborneyl, dekalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, etc. Furthermore, the term cycloalkyl is intended to encompass any non-aromatic ring system that may contain a fused aryl ring regardless of its bonding to the rest of the molecule. Also further, cycloalkyl also includes "spirocycloalkyl," such as spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl. If, in the parent structure, there are two positions on the carbon atom relative to the substitution, the cycloalkyl as a substituent may also include spirocycloalkyl. The cycloalkyl group may be substituted at the carbon atom of the bond to the parent structure.

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

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

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

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

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

[0050] "Halogen" or "halo" refers to substituted atoms in Group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodine.

[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, including all hydrogen atoms and all hydrogen atoms, are replaced by halogens. 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 bonded. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted with two ("di") or three ("tri") halo groups, which may or may not be the same halogen. Perhaloalkyl groups are haloalkyl groups in which all hydrogen substituents are replaced by halos. Examples of haloalkyl groups include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0052] A "haloalkoxy" refers to an alkoxy group as defined above, in which all hydrogen atoms and one or more hydrogen atoms (e.g., 1 to 6 or 1 to 3) including all hydrogen atoms are replaced by halogens.

[0053] A "hydroxyalkyl" group refers to an alkyl group as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a hydroxyl group.

[0054] A "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) of the alkyl chain are independently replaced by the same or different heteroatomic groups, provided that the bonding sites to the rest of the molecule are via carbon atoms. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. For example, one, two, or three carbon atoms may be independently replaced by the same or different heteroatomic groups. Examples of heteroatomic groups include, but are not limited to, -NR y -, -C(O)NR y -, -NRy C(O)-, -O-, -S-, -S(O)-, -S(O)2-, etc. (in the formula, R y Examples of heteroalkyl groups include hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be substituted as defined herein. Examples of heteroalkyl groups include, for example, ethers (e.g., -CH2OCH3, -CH(CH3)OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, etc.), thioethers (e.g., -CH2SCH3, -CH(CH3)SCH3, -CH2CH2SCH3, -CH2CH2SCH2CH2SCH3, etc.), sulfones (e.g., -CH2S(O)2CH3, -CH(CH3)S(O)2CH3, -CH2CH2S(O)2CH3, -CH2CH2S(O)2CH3, etc.) and aminoalkyl groups (e.g., -CH2NR y CH3, -CH(CH3)NR y CH3, -CH2CH2NR y CH3, -CH2CH2NR y CH2 CH2NR y CH3, etc., here, R y Examples include hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be substituted as defined herein. As used herein, a heteroalkyl comprises 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] A "heteroaryl" is a ring heteroatom in which one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur, and one or more (e.g., 1 to 3) N-oxides (-O) - This refers to an aromatic group having a monocyclic or polycyclic fused ring that may include a portion of the ring. As used herein, heteroaryl refers to an aromatic group having 1 to 20 ring carbon atoms (i.e., C 1~20(heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3~12 (heteroaryl), or 3 to 8 carbocyclic atoms (i.e., C 3~8A heteroaryl comprises a heteroaryl ring and one to five ring heteroatoms, one to four ring heteroatoms, one to three ring heteroatoms, one to two ring heteroatoms, or one ring heteroatom, independently selected from nitrogen, oxygen, and sulfur. In certain cases, the heteroaryl ring comprises a 5 to 10-membered ring system, a 5 to 7-membered ring system, or a 5 to 6-membered ring system, each independently having one to four ring heteroatoms, one to three ring heteroatoms, one to two ring heteroatoms, or one ring heteroatom, 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, sinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, Examples include soquinoryl, isoxazolyl, naphthilidinyl, oxadiazolyl, oxazolyl, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyradinyl, 1-oxidepyradinyl, 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, though not limited to these, include benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bonded via any of the rings in the fused system. Any aromatic ring system having a single or multiple fused ring containing at least one heteroatom, regardless of its bond to the rest of the molecule (i.e., via any one of the fused rings), can be considered a heteroaryl. Heteroaryls do not encompass or overlap with the aryls as defined above.

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

[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, and the nitrogen or sulfur atom may be oxidized in some cases 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. Heterocyclyl may be monocyclic or polycyclic, and the polycycle may be fused, bridged, or spiro. Regardless of the listed substituents, heterocyclyl, unless otherwise expressly stated, contains one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O - ) moieties. Heterocyclyl can be bonded through a carbon atom or a heteroatom as long as the valence allows. Further, the term heterocyclyl encompasses any ring system containing a non-aromatic ring having at least one heteroatom, and this ring may be fused to an aryl or heteroaryl ring regardless of the bond to the rest of the molecule. Heterocyclyl may have a charged resonance structure that is aromatic (e.g., pyridin-2(1H)-on-1-yl). As used herein, heterocyclyl has 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 3~6It may contain heterocyclyl groups, and may have 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom. Examples of heterocyclyl groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxynyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolidinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindo Examples include lyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxylanil, oxetanil, phenothiazinyl, phenoxadinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianil, 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. In the parent structure, if there are two positions on the carbon atom for a substitution, the heterocyclyl substituent may include a spiroheterocyclyl. Examples of bridging heterocyclyl rings, but not limited to these, include 2,5-diazabicyclo[2.2.1]heptane and 2-oxa-5-azabicyclo[2.2.1]heptanyl.Examples of condensed heterocyclyl rings, though not limited to these, include 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be linked via any of the rings in the condensation system. An "oxo-heterocyclyl" group is a heterocyclyl containing at least one oxo substituent (e.g., 1, or 1-2 oxo substituents), whether or not additional substituents are allowed (i.e., an unsubstituted oxo-heterocyclyl contains an oxo substituent and no other substitutions). In some embodiments, the oxo-heterocyclyl contains a cyclic amide moiety.

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

[0059] "Oxime" is -CR y (=NOH) group (wherein R y is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl, each of which may be substituted as defined herein.

[0060] "Sulfonyl" is -S(O)2R y group (in the formula, R y is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl, each of which may be substituted as defined herein. Examples of sulfonyls are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and toluenesulfonyl.

[0061] "Sulfinyl" is -S(O)R y group (in the formula, R yis hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl, each of which may be 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 Each of these independently refers to hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl (each of which may be substituted as defined herein).

[0063] The terms "depending on the circumstances" or "depending on the circumstances" mean that the event or situation described thereafter may or may not occur, and that the description includes both cases in which the event or situation occurs and cases in which it does not occur. Furthermore, the term "substituted depending on the circumstances" refers to the base of either the non-substitution or the substitution.

[0064] As used herein, the term "substituted" means that one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are substituted for a non-hydrogen group, e.g., but not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amide, amino, amidino, aryl, arylalkyl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH2, =NNH2, imino, imide, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)2OH, sulfonamide, thiol, thioxo, N-oxide, or -Si(R y )3(in the formula, each R y This refers to a group that is independently replaced by hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0065] In certain embodiments, "substituted" means that one or more (e.g., 1-5 or 1-3) hydrogen atoms are independently deuterium, halo, cyano, hydroxyl, imino, nitro, azide, 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 Ure g , -NR g S(=O) 1-2 NR g R h ,=NSO2R g 、=NOR g -S(=O) 1-2 NR g R h This refers to a group that is replaced with -SF5 or -SCF3. In certain embodiments, "substituted" also means that one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced with -C(=O)R g , -C(=O)OR g -C(=O)NR g R h ,-CH2SO2R g , or -CH2SO2NR g R h It means the base that is replaced by R. g and R h These are the same or different, independently of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl, or R g and R h These, together with the atoms to which they are bonded, form an oxo, halo, or optionally alkyl-substituted heterocyclyl ring, which may be substituted with an oxo, halo, amino, hydroxyl, or alkoxy.

[0066] Polymers or similar indeterminate structures achieved by defining substituents having an infinitely increasing number of further substituents (e.g., substituted aryls having a substituted alkyl that itself is substituted with a substituted aryl group (which is further substituted with a substituted heteroalkyl group, etc.)) are not intended to arise from the above definition. Unless otherwise explicitly stated, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group having two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryls. Similarly, the above definition is not intended to include compounds having substitution patterns that are chemically impossible or inseparable (e.g., a methyl group substituted with five fluorine atoms or a heteroaryl group having three consecutive oxygen ring atoms). Such unacceptable substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term “substituted” may describe other chemical groups as 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 described herein is intended to represent both the unlabeled form of the compound and its “isotope-enriched analogue.” The isotope-enriched form of a compound may also be referred to as “labeled.” An isotope-enriched analogue has the structure described 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, for example, respectively. 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 I is one example. Isotopic-enriched analogues generally include compounds having any isotopic enrichment above the natural abundance of the isotope (e.g., on the Earth's surface). Various isotopic-labeled compounds, e.g., radioactive isotopes, e.g., 3 H, 18 F, 11 C, and 14 This disclosure includes things like the incorporation of C. 18 F, 3 H, or 11 Compounds labeled with 1C may be useful in metabolic experiments, reaction kinetics experiments, 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 radiotherapy for patients.

[0069] The term “isotope-enriched analog” includes “deuterated analogs” of the compounds described herein, in which one or more hydrogen atoms, for example, a hydrogen atom on a carbon atom, are replaced by deuterium. Such compounds can exhibit increased resistance to metabolism and may therefore be useful in increasing the half-life of any compound when administered to mammals, particularly humans. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci., Vol. 5(No. 12): pp. 524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogen atoms are replaced by deuterium.

[0070] Therapeutic compounds of the present disclosure that are deuterium-labeled or substituted may have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism, and elimination (ADME). Substitution with heavier isotopes, such as deuterium, may result in certain therapeutic advantages resulting from higher metabolic stability, such as increased in vivo half-life, reduced dose required, and / or improved therapeutic index. The isotope-labeled compounds of the present disclosure and their prodrugs can generally be prepared by substituting the non-isotope-labeling reagent with a readily available isotope-labeling reagent, by performing the procedures disclosed in the schemes described below or in the examples and preparations. The isotope-labeled compounds of the present disclosure and their pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, and mixtures of stereoisomers can generally be prepared by substituting the non-isotope-labeling reagent with a readily available isotope-labeling reagent, by performing the procedures disclosed in the schemes described below or in the examples and preparations. Where a compound is described as a deuterated analogue, the compound may be described 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 this disclosure, any atom not specifically indicated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, where a position is specifically designated as "H" or "hydrogen," this position is considered to contain hydrogen and its isotopes in their natural abundances.

[0072] In many cases, the compounds of this disclosure can form acids and / or base salts in the presence of amino and / or carboxyl groups or similar groups.

[0073] Isotope-enriched analogs, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, and mixtures of stereoisomers of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other materials useful for preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0074] In this specification, the term "pharmaceutically acceptable salt" of a compound means a salt that retains the biological efficacy and properties of a given compound and is not biologically or otherwise inappropriate. "pharmaceutically acceptable salts" or "physiologically acceptable salts" of 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. When a compound is obtained as an acid addition salt, the free base can be obtained by basicizing a solution of the acidic salt. Conversely, when a compound is a free base (e.g., an amine compound), the addition salt can be produced by dissolving the free base in a suitable organic solvent and treating this 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 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, and phosphoric acid. 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, and salicylic acid. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Examples of salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts.Salts derived from organic bases are not limited to these, but include 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), and tri(substituted alkenyl)amines (i.e., N(substituted alkyl)). Examples of suitable amines include salts of monocycloalkylamines, dicycloalkylamines or tricycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), monoarylamines, diarylamines or triarylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), cyclic amines (e.g., piperidine, piperazine, 1,4-diazabicyclo[2.2.2]octane), aromatic amines (e.g., pyridine, quinoline), or mixed amines. Specific examples of suitable amines, by definition only, include isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, and N-ethylpiperidine.

[0075] Some of the compounds described herein may exist as tautomers. For example, if a compound is described as containing an amide, the compound may also exist as an imido acid tautomer, and if a compound is described as containing a ketone, the compound may also exist as an enol tautomer. Regardless of which tautomer is shown, and regardless of the equilibrium properties between the tautomers, the compound is understood by those skilled in the art to contain both tautomers. Thus, for example, a compound containing an amide is understood to contain these imido acid tautomers, and a compound containing an imido acid is understood to contain these amide tautomers.

[0076] The compounds described herein may contain chiral centers and thus give rise to enantiomers, diastereomers, and other stereoisomers that can be defined as (R)- or (S)-, or (D)- or (L)- with respect to an amino acid in terms of absolute stereochemistry. The compounds described herein are intended 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 they may be resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include, for example, chiral synthesis from a suitable optically pure precursor or racemic resolution (or racemic salt or derivative) using chiral high-performance liquid chromatography (HPLC). If the compounds described herein contain a double bond or other geometrically asymmetric centers, and unless otherwise specified, the compounds are intended to include both cis- and trans- or E- and Z- geometric isomers.

[0077] A "stereoisomer" refers to one of a set of compounds that have different three-dimensional structures despite being composed of the same atoms bonded together by the same bonds. Various stereoisomers and mixtures thereof are assumed to include "enantiomers," which are stereoisomer compounds that are mirror images of each other and cannot be superimposed. A "diastereomer" is one of a set of stereoisomers that have at least two asymmetric atoms that are not mirror images of each other.

[0078] A “prodrug” is any molecule that, when administered to a mammalian subject, releases a parent drug that is presumed to be active in vivo by the compounds described herein. A prodrug may be any form of a compound described herein that has been modified so that the modification can be cleaved in vivo to release the parent compound. Prodrugs can be prepared by modifying a functional group present in a compound described herein so that the modification can be cleaved into the parent compound either by conventional procedures or in vivo. Prodrugs include compounds described herein in which a hydroxy, amino, carboxyl, or sulfhydryl group in the compound described herein is bonded to any group that can be cleaved in vivo to regenerate a 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, and carbamates (e.g., N,N-dimethylaminocarbonyl) such as hydroxyl 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, respectively, the entirety of which is incorporated herein by reference.

[0079] In some embodiments, the term “neurodegenerative disease” refers to a disease or condition in which the function of the nervous system in question is impaired. Examples of neurodegenerative diseases are 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 organism, such as an animal or a human. In this context, the methods described herein can be used therapeutically in an organism. “Ex vivo” means outside a living organism. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from organisms. 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 the optimal schedule and / or dosage of the compounds disclosed for a given symptom, cell type, organism, and other parameters. Information gathered from such use can be used clinically for experimental purposes or to establish 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 skilled in the art. The selected compounds can be further characterized to investigate their safety or tolerable dose in human or non-human subjects. Such properties can be investigated using methods generally known to those skilled in the art.

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

[0082] In this specification, the terms “group,” “part,” “radical,” “substituent,” and “fragment” are synonymous and are intended to refer to a part of a molecule that can be bonded to another part of the molecule, for example, via the indicated bond or bond.

[0083] The term “active agent” is used to refer to a compound that has biological activity in the treatment, remission, or prevention of a disease or condition. In some embodiments, an “active agent” is a compound with pharmaceutically useful properties or its isotope-labeled analogues, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers. For example, an active agent may be an antineurodegenerative agent.

[0084] The term “effective dose” means the amount of a compound described herein that is sufficient to produce a desired response in an individual or patient. In relation to the use of imaging agents, the effective dose may be the amount required to produce an image that has diagnostic or therapeutic utility. The term “therapeutic effective dose” means the amount that, when administered to a human or non-human patient, is effective in conferring a therapeutic benefit such as remission of symptoms, delay of disease progression, or prevention of disease. For example, the therapeutic effective dose may be the amount sufficient to reduce the symptoms of the disease described herein. The (therapeutic) effective dose may vary depending on the subject being treated, the disease or condition, the subject’s weight and age, the severity of the disease or condition, and the method of administration, and can be readily determined by those skilled 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) located on the short (p) arm of chromosome 4 at position 16.3. More precisely, the IT encoding the HTT protein. 15 The genes are located on chromosome 4, specifically at base pairs 3,076,407 to 3,245,686.

[0086] As used herein, the term "protein aggregate" refers to the aggregation of proteins, which may include, for example, insoluble fibrous amyloids containing misfolded HTT protein molecules ("HTT protein aggregates") or misfolded β-amyloid protein molecules ("β-amyloid aggregates"). A "protein prone to aggregation" 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, or a composition comprising a labeled compound, that is labeled with one or more positron-emitting isotopes or radionuclides. The positron-emitting labeled compound only needs to be enriched with detectable isotopes to the extent that it can be detected using techniques suitable for the particular application.

[0088] The term "PET imaging" (also known as positron emission tomography imaging), as used herein, refers to the generation of images of the internal structures of a human or animal body using positron-emitting labeled compounds.

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

[0090] As used herein, the term “labeled” refers to a compound associated with one or more positron-emitting radionuclides at a greater abundance than in nature. For example, the labeled compounds described herein may contain one or more positron-emitting radionuclides in which atoms in the molecule (including any of the substituents shown) exist as positron-emitting isotopes.

[0091] As used herein, the term "tomography" refers to the imaging method for each section. The images can be viewed individually as a series of two-dimensional sections, or together as a computer-generated three-dimensional representation.

[0092] In some embodiments, the term “neurodegenerative disease” refers to a disease or condition in which the function of the nervous system in question is impaired. Examples of neurodegenerative diseases are those described herein.

[0093] "Treatment" or "to treat" means any treatment of a patient's disease condition. a) To inhibit the disease (for example, to reduce one or more symptoms resulting from the disease or condition, and / or to reduce the extent of the disease or condition); b) Delaying or cessation of the onset of clinical signs associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread of the disease or condition (e.g., metastasis)); and / or c) To alleviate the disease, that is, to bring about a regression of clinical signs (e.g., to bring the condition into remission, to provide partial or complete remission of the disease or condition, to enhance the action of another drug, to slow the progression of the disease, to increase the quality of life and / or prolong life). Includes.

[0094] "Prevention" or "prevention" means any treatment of a disease or condition that prevents the development of clinical signs of the disease or condition. In some embodiments, the compound may be administered to subjects (including humans) who are at risk (e.g., have genetic or epigenetic markers, have been engaged in activities related to the disease or condition, or have been exposed to environmental conditions) or who have a family history of the disease or condition.

[0095] "Subject" or "patient" refers to an animal, such as a mammal, that is or will be the subject of treatment, observation, or experimentation. The methods described herein may be useful in both human therapeutic and veterinary applications. In some embodiments, the subject or patient is a mammal. In some embodiments, the subject or patient is a human.

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

[0097] As used herein, the term "diagnostic imaging" refers to the use of electromagnetic radiation to generate images of the internal structures of a human or animal body for diagnostic purposes.

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

[0099] [Table 1] TIFF2026053514000002.tif238149TIFF2026053514000003.tif238149TIFF2026053514000004.tif50150

[0100] compound This disclosure relates to compounds useful for imaging proteins that are prone to aggregation, such as huntingtin protein.

[0101] Some embodiments use formula I':

[0102] [ka] [A 1 is C; A 2 is C or N; A 3 CR 21 , NR 3 , or N; A 4 CR 22 , NR 3 , or N; A 5 CR 23 , NR 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 of these independently consists of hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C. 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy or C 3~6 It is a cycloalkyl; Each R 3 These are, independently, hydrogen and C 1~4 Alkyl, C 1~4 Haloalkyl, or C 3~6 It is a cycloalkyl; A 6 CR 11 Or N, A 7 CR 12 Or N, A 8 CR 13 Or N, A 9 CR 14 Or N, A 6 , A 7 , A 8 , and A 9 Two or fewer of these are N; R 11 , R12 , R 13 , and R 14 Each of these is 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 It is alkyl)3; X 1 is C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 It is an aryl, heteroaryl, or heterocyclyl, and X 1 1 to 4 R 4 It is sometimes replaced by; Each R 4 These are independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and 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 1-3 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 It is an alkoxy; L is -(C(R 6 )2) m -where m is 1, 2, 3, or 4; Each R 6 These are independently hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 It is a haloalkoxy, or two R 6 It can link with any intervening atom to form a 3-6 membered ring; L 1 is C(O), C(O)NR a , NR a C(O), or O, or L 1 It does not exist; R a is hydrogen, C 1~6 Alkyl, or C 1~6 It is a haloalkyl; L 2 These are 1 to 4 R's 7 C is sometimes replaced by 1~2 It is alkylene, or L 2 It does not exist; Each R 7 These are independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 [It is a haloalkoxy] The present invention provides compounds that are labeled with one or more radioactive isotopes, or isotope-enriched analogs thereof, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers.

[0103] Some embodiments use formula I':

[0104] [ka] [A 1 is C; A 2 is C or N; A 3 CR 21 , NR 3 , or N; A 4 CR 22 , NR 3 , or N; A 5 CR 23 , NR 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 of these independently consists of hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C. 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy or C 3~6 It is a cycloalkyl; Each R 3 These are, independently, hydrogen and C 1~4 Alkyl, C 1~4 Haloalkyl, or C 3~6 It is a cycloalkyl; A 6 CR 11 Or N, A 7 CR 12 Or N, A 8 CR 13 Or N, A 9 CR 14 Or N, A 6 , A 7 , A 8 , and A 9 Two or fewer of these are N; R 11 , R 12 , R 13 , and R 14 Each of these is 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 It is alkyl)3; X 1 is C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 It is an aryl, heteroaryl, or heterocyclyl, and X 1 1 to 4 R4 It is sometimes replaced by; Each R 4 These are independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and 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 1-3 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 It is an alkoxy; L is -(C(R 6 )2) m -where m is 1, 2, 3, or 4; Each R 6 These are independently hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 It is a haloalkoxy, or two R 6 It can link with any intervening atom to form a 3-6 membered ring; L 1 is C(O), C(O)NR a , NR a C(O), or O, or L 1 It does not exist; R a is hydrogen, C 1~6 Alkyl, or C 1~6 It is a haloalkyl; L 2 These are 1 to 4 R's 7 C is sometimes replaced by 1~2 It is alkylene, or L 2 It does not exist; Each R 7These are independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 [It is a haloalkoxy] The present invention provides compounds that are optionally labeled with one or more radioactive isotopes, or isotopic-enriched analogs thereof, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers.

[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-(pyrroridine-1-yl)butyl)pyrrolo[1,2-a]quinoxaline-4(5H)-one, N-(2,4-dimethoxyphenyl)-3-(4-oxopyrrolo[1,2-a]quinoxaline-5(4H)-yl)propanamide, 7-fluoro-5-[4-(morpholin-4-yl)-4-oxobutyl]-4H,5H-pyrrolo[1,2-a]quinoxaline-4-one, 5-[4-(3,5-dimethylpiperidine-1-yl)-4- It is not 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-(piperidine-1-yl)butyl]-4H,5H-pyrrolo[1,2-a]quinoxalin-4-one, or 7-fluoro-5-[2-oxo-2-(piperidine-1-yl)ethyl]-4H,5H-pyrrolo[1,2-a]quinoxalin-4-one.

[0107] Some embodiments use formula I:

[0108] [ka] [A 1 is C; A 2is C or N; A 3 CR 21 , NR 3 , or N; A 4 CR 22 , NR 3 , or N; A 5 CR 23 , NR 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 of these independently consists of hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C. 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy or C 3~6 It is a cycloalkyl; Each R 3 These are, independently, hydrogen and C 1~4 Alkyl, C 1~4 Haloalkyl, or C 3~6 It is a cycloalkyl; A 6 CR 11 Or N, A 7 CR 12 Or N, A 8 CR 13 Or N, A 9 CR 14 Or N, A 6 , A 7 , A 8 , and A 9 Two or fewer of these are N; R 11 , R 12 , R 13 , and R 14Each of these is hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 It is a haloalkoxy; X 1 is C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 It is an aryl, heteroaryl, or heterocyclyl, and X 1 1 to 4 R 4 It is sometimes replaced by; Each R 4 These are independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 It is a 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 It is an alkoxy; L is -(C(R 6 )2) m -where m is 1, 2, 3, or 4; Each R 6 These are independently hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 It is a haloalkoxy, or two R 6 It can link with any intervening atom to form a 3-6 membered ring; L 1 is C(O), C(O)NR a , NR a C(O), or O, or L 1 It does not exist; R a is hydrogen, C1~6 Alkyl, or C 1~6 It is a haloalkyl; L 2 These are 1 to 4 R's 7 C is sometimes replaced by 1~2 It is alkylene, or L 2 It does not exist; Each R 7 These are independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 [It is a haloalkoxy] The present invention provides compounds that are optionally labeled with one or more radioactive isotopes, or isotopic-enriched analogs thereof, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers.

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

[0110] In some embodiments, the compound is 7-bromo-5-(4-oxo-4-(pyrroridine-1-yl)butyl)pyrrolo[1,2-a]quinoxaline-4(5H)-one, N-(2,4-dimethoxyphenyl)-3-(4-oxopyrrolo[1,2-a]quinoxaline-5(4H)-yl)propanamide, 7-fluoro-5-[4-(morpholin-4-yl)-4-oxobutyl]-4H,5H-pyrrolo[1,2-a]quinoxaline-4-one, 5-[4-(3,5-dimethylpiperidine-1-yl)-4- It is not 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-(piperidine-1-yl)butyl]-4H,5H-pyrrolo[1,2-a]quinoxalin-4-one, or 7-fluoro-5-[2-oxo-2-(piperidine-1-yl)ethyl]-4H,5H-pyrrolo[1,2-a]quinoxalin-4-one.

[0111] In some embodiments, formula I: [In the formula, A 1 is C; A 2 is C or N; A 3 CR 21 , NR 3 , or N; A 4 CR 22 , NR 3 , or N; A 5 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 of these independently consists of hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C. 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy or C 3~6 It is a cycloalkyl; Each R 3 These are, independently, hydrogen and C 1~4 Alkyl, C 1~4 Haloalkyl, or C 3~6 It is a cycloalkyl; A 6 CR 11 Or N, A 7 CR 12 Or N, A 8 CR 13 Or N, A 9 CR 14 Or N, A 6 , A 7 , A 8 , and A 9 One of them less than or equal to N is; R 11 , R 12 , R 13 , and R 14 Each of these is hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 It is a haloalkoxy; X 1 is C 3~10 Cycloalkyl, C 6~10 It is an aryl, heteroaryl, or heterocyclyl, and X 1 1 to 4 R 4 It is sometimes replaced by; Each R 4 These are independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 It is a 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 It is an alkoxy; L is -(C(R 6 )2) m -where m is 2, 3, or 4; Each R 6 These are independently hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 It is a haloalkoxy; L 1 is C(O), C(O)NR a Or NR a C(O) is; R a is hydrogen, C 1~6 Alkyl, or C 1~6It is a haloalkyl; L 2 These are 1 to 4 R's 7 C is sometimes replaced by 1~2 It is alkylene, or L 2 It does not exist; Each R 7 These are independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 [It is a haloalkoxy] A compound of, Provided are compounds other than 7-bromo-5-(4-oxo-4-(pyrroridine-1-yl)butyl)pyrrolo[1,2-a]quinoxaline-4(5H)-one or N-(2,4-dimethoxyphenyl)-3-(4-oxopyrrolo[1,2-a]quinoxaline-5(4H)-yl)propanamide, or isotopic-enriched analogs thereof, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers.

[0112] In some embodiments, formula I:

[0113] [ka] [In the formula, A 1 is C; A 2 is C or N; A 3 CR 21 , NR 3 , or N; A 4 CR 22 , NR 3 , or N; A 5 CR 23 and; -A 1 -A 2 -A 3 -A 4 -A 5The ring Z formed by - is a 5-membered heteroaryl having up to 3 nitrogen atoms; R 21 , R 22 , and R 23 Each of these independently consists of hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C. 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy or C 3~6 It is a cycloalkyl; Each R 3 These are, independently, hydrogen and C 1~4 Alkyl, C 1~4 Haloalkyl, or C 3~6 It is a cycloalkyl; A 6 CR 11 Or N, A 7 CR 12 Or N, A 8 CR 13 Or N, A 9 CR 14 Or N, A 6 , A 7 , A 8 , and A 9 One of them less than or equal to N is; R 11 , R 12 , R 13 , and R 14 Each of these is hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 It is a haloalkoxy; X 1 is C 3~10 Cycloalkyl, C 6~10 It is an aryl, heteroaryl, or heterocyclyl, and X 1 1 to 4 R 4 It is sometimes replaced by; Each R 4These are independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 It is a 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 It is an alkoxy; L is -(C(R 6 )2) m -where m is 2, 3, or 4; Each R 6 These are independently hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 It is a haloalkoxy; L 1 is C(O), C(O)NR a Or NR a C(O) is; R a is hydrogen, C 1~6 Alkyl, or C 1~6 It is a haloalkyl; L 2 These are 1 to 4 R's 7 C is sometimes replaced by 1~2 It is alkylene, or L 2 It does not exist; Each R 7 These are independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 [It is a haloalkoxy] A compound of, Provided are compounds other than 7-bromo-5-(4-oxo-4-(pyrroridine-1-yl)butyl)pyrrolo[1,2-a]quinoxaline-4(5H)-one or N-(2,4-dimethoxyphenyl)-3-(4-oxopyrrolo[1,2-a]quinoxaline-5(4H)-yl)propanamide, or isotopic-enriched analogs thereof, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers.

[0114] In some embodiments, formula I: [In the formula, A 1 is C; A 2 is C or N; A 3 CR 21 , NR 3 , or N; A 4 CR 22 , NR 3 , or N; A 5 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 of these independently consists of hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C. 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy or C 3~6 It is a cycloalkyl; Each R 3 These are, independently, hydrogen and C 1~4 Alkyl, C 1~4 Haloalkyl, or C 3~6 It is a cycloalkyl; A 6 CR11 Or N, A 7 CR 12 Or N, A 8 CR 13 Or N, A 9 CR 14 Or N, A 6 , A 7 , A 8 , and A 9 One of them less than or equal to N is; R 11 , R 12 , R 13 , and R 14 Each of these is hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 It is a haloalkoxy; X 1 is C 3~10 Cycloalkyl, C 6~10 It is an aryl, heteroaryl, or heterocyclyl, and X 1 1 to 4 R 4 It is sometimes replaced by; Each R 4 These are independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 It is a 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 It is an alkoxy; L is -(C(R 6 )2) m -where m is 2, 3, or 4; Each R 6 These are independently hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C 1~4Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 It is a haloalkoxy; L 1 is C(O), C(O)NR a Or NR a C(O) is; R a is hydrogen, C 1~6 Alkyl, or C 1~6 It is a haloalkyl; L 2 These are 1 to 4 R's 7 C is sometimes replaced by 1~2 It is alkylene, or L 2 It does not exist; Each R 7 These are independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 [It is a haloalkoxy] A compound of, It is not 7-bromo-5-(4-oxo-4-(pyrroridine-1-yl)butyl)pyrrolo[1,2-a]quinoxaline-4(5H)-one or N-(2,4-dimethoxyphenyl)-3-(4-oxopyrrolo[1,2-a]quinoxaline-5(4H)-yl)propanamide, but 7-fluoro-5-[4-(morpholin-4-yl)-4-oxobutyl]-4H,5H-pyrrolo[1,2-a]quinoxaline-4-one, 5-[4-(3,5-dimethylpiperidine-1-yl)-4-oxobutyl]- Compounds other than 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-(piperidine-1-yl)butyl]-4H,5H-pyrrolo[1,2-a]quinoxalin-4-one, or isotopic-enriched analogs thereof, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers are provided.

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

[0116] [ka] The compound, or its isotope-enriched analogues, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers.

[0117] In some embodiments, the compound of formula I is formula IIa:

[0118] [ka] [R b ha-L 2 -X 1 And R a This is as defined herein; or R a and R b It has 1 to 4 R atoms along with any intervening atom. 4 [This may result in the formation of a 3- to 10-membered heterocyclyl ring which is substituted in some cases.] The compound, or its isotope-enriched analogues, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers.

[0119] In some embodiments, the compound of formula I is formula IIb:

[0120] [ka] [R b ha-L 2 -X 1 And R a This is as defined herein; or R a and R b It has 1 to 4 R atoms along with any intervening atom. 4 [This may result in the formation of a 3- to 10-membered heterocyclyl ring which is substituted in some cases.] The compound, or its isotope-enriched analogues, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers.

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

[0122] [ka] [R b ha-L 2 -X 1 And R a This is as defined herein; or R a and R b It has 1 to 4 R atoms along with any intervening atom. 4 [This may result in the formation of a 3- to 10-membered heterocyclyl ring which is substituted in some cases.] The compound, or its isotope-enriched analogues, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers.

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

[0124] [ka] [R b ha-L 2 -X 1 And R a This is as defined herein; or R a and R b It has 1 to 4 R atoms along with any intervening atom. 4 [This may result in the formation of a 3- to 10-membered heterocyclyl ring which is substituted in some cases.] The compound, or its isotope-enriched analogues, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers.

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

[0126] In some embodiments, R 11 , R 12 , R 13 , and R 14 This refers to radioactive isotopes, for example, 18 Other known functional groups may be used for introducing F. Examples of such functional groups, but are not limited to, include boron derivatives and NO2 derivatives.

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

[0128] In some embodiments, R 21 , R 22 , and R 23 One of them is methyl. In some embodiments, R 21 , R 22 , and R 23 One of them is a halo. In some embodiments, R 21 , R 22 , and R 23One of them is fluoro. In some embodiments, R 21 , R 22 , and R 23 Each of them is hydrogen.

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

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

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

[0132] In some embodiments, X 1 is a heteroaryl. In some embodiments, X 1 These are pyridine-2-yl, pyridine-3-yl, or pyridine-4-yl.

[0133] In some embodiments, X 1 is a heterocycline. In some embodiments, X 1 is 1-piperidinyl, 4-morpholinyl, piperazine-1-yl, piperazine-3-on-1-yl, pyrrolidine-1-yl, or pyridazine-3(2H)-on-6-yl. In some embodiments, X 1 It is an oxo-heterocycline.

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

[0135] In some embodiments, X 1 is phenyl, and R 4 is 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 X is 2,4-difluorophenyl. In some embodiments, X 1 It is 2,5-difluorophenyl.

[0137] In some embodiments, R a and R b It has 1 to 4 R atoms along with any intervening atom. 4 This forms a 3- to 10-membered heterocyclyl ring which may be substituted by R. In some embodiments, a and R b It has 1 to 4 R atoms along with any intervening atom. 4 This may result in the formation of 1-piperidinyl, 4-morpholinyl, piperazine-1-yl, piperazine-3-on-1-yl, pyrrolidine-1-yl, or pyridazine-3(2H)-on-6-yl, which are substituted as such.

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

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

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

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

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

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

[0144] In some embodiments, compounds selected from the compounds in Table 1A, optionally labeled with one or more radioisotopes, or isotopic-enriched analogs thereof, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers are provided. In some embodiments, compounds selected from the compounds in Table 1B, optionally labeled with one or more radioisotopes, or isotopic-enriched analogs thereof, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers are provided.

[0145] In some embodiments, the compound of formula I is labeled with one or more radioactive isotopes.

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

[0147] In some embodiments, imaging agents are provided comprising a compound of formula I', or an isotope-enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers.

[0148] Additional compounds described herein are also provided. In some embodiments, compounds selected from Table 1A, or their isotopically labeled analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers are provided.

[0149] In some embodiments, pharmaceutical compositions are provided that include compounds described herein, or isotopic-enriched analogs thereof, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers, and pharmaceutically acceptable excipients.

[0150] Nonmetallic radionuclides can be covalently bonded to the compounds described herein by reactions known from the latest technology. 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 from the latest technology.

[0151] In some embodiments, compounds selected from the compounds described in the Examples section provided herein are provided.

[0152] Compounds selected from Table 1A, or their isotope-enriched analogs, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers are also provided:

[0153] [Table 2] TIFF2026053514000015.tif211153TIFF2026053514000016.tif211153TIFF2026053 514000017.tif211153TIFF2026053514000018.tif211153TIFF2026053514000019.t if211153TIFF2026053514000020.tif211153TIFF2026053514000021.tif211153TIF F2026053514000022.tif211153TIFF2026053514000023.tif211153TIFF20260535140 00024.tif211153TIFF2026053514000025.tif211153TIFF2026053514000026.tif21 1153TIFF2026053514000027.tif211153TIFF2026053514000028.tif211153TIFF202 6053514000029.tif211153TIFF2026053514000030.tif211153TIFF20260535140000 31.tif211153TIFF2026053514000032.tif211153TIFF2026053514000033.tif114153

[0154] The compounds listed in Table 1B, or their isotope-enriched analogues, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers are as follows:

[0155] [Table 3]

[0156] Diagnostic methods and use In some embodiments, a method is provided for generating a diagnostic image in an individual, comprising administering an effective amount of a compound or imaging agent described herein to the individual, and generating an image of a body part or region of the individual. Generating an image of a body part or region of the individual may include generating an image and detecting the presence or absence of proteins prone to aggregation in the image. Thus, the compounds disclosed herein are useful for detecting diseases or conditions at least partially mediated by proteins prone to protein aggregation. In some embodiments, the presence or absence of protein aggregates corresponds to the presence or absence of neurodegenerative diseases. In some embodiments, neurodegenerative diseases are selected from Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, prion diseases, and spinocerebellar ataxia.

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

[0158] In some embodiments, a method for generating a diagnostic image in an individual, wherein the effective quantity is given by formula I:

[0159] [ka] [A 1 is C; A 2 is C or N; A 3 CR 21 , NR 3 , or N; A 4 CR 22 , NR 3 , or N; A 5 CR 23 , NR 3 , or N; -A 1 -A2 -A 3 -A 4 -A 5 - The ring Z formed thereby is a 5-membered heteroaryl having up to 3 nitrogen atoms; R 21 ,R 22 ,and R 23 each independently is 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 cycloalkyl; Each R 3 independently is hydrogen, C 1~4 alkyl, C 1~4 haloalkyl, or C 3~6 cycloalkyl; A 6 is CR 11 or N, A 7 is CR 12 or N, A 8 is CR 13 or N, A 9 is CR 14 or N, A 6 ,A 7 ,A 8 ,and A 9 two or less of them are N; R 11 ,R 12 ,R 13 ,and R 14 each independently is 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 s 4It is sometimes replaced by; Each R 4 These are independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 It is a 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 It is an alkoxy; L is -(C(R 6 )2) m -where m is 1, 2, 3, or 4; Each R 6 These are independently hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 It is a haloalkoxy, or two R 6 It can link with any intervening atom to form a 3-6 membered ring; L 1 is C(O), C(O)NR a , NR a C(O), or O, or L 1 It does not exist; R a is hydrogen, C 1~6 Alkyl, or C 1~6 It is a haloalkyl; L 2 These are 1 to 4 R's 7 C is sometimes replaced by 1~2 It is alkylene, or L 2 It does not exist; Each R 7 These are independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4Alkoxy, or C 1~4 [It is a haloalkoxy] A method is provided comprising administering a compound, optionally labeled with one or more radioactive isotopes, or an isotope-enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers.

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

[0161] A method for generating diagnostic images using positron emission tomography (PET) is provided. PET imaging may be carried out as known to those skilled in the art, or as described below. PET imaging may involve administering a positron-emitting radionuclide tracer, e.g., a compound or imaging agent described herein, to an individual. The tracer is then allowed to bind to a target protein for a sufficient amount of time, at which point the individual is placed in a scanning apparatus equipped with a scintillation detector ring. The emitted positron travels a short (isotope-dependent) distance within the individual's tissue until it interacts with an electron. This interaction annihilates both the electron and the positron, producing a pair of photons. The photons are detected by a scintillator in the scanning apparatus. Photons that do not form a pair are ignored.

[0162] Methods for generating diagnostic images are also provided, 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] Therefore, the compounds or imaging agents described herein can be administered by methods known in the art, including those described herein. The compounds or imaging agents can enter the circulation and bind to proteins that are prone to aggregation, or to aggregates thereof. When the compounds or imaging agents are labeled with radioisotopes, the released particles can be detected.

[0164] In some embodiments, the compound or imaging agent is administered into the vascular system of an individual. The compound or imaging agent can cross the blood-brain barrier. Therefore, generating an image may involve generating an image of at least a portion of the individual's brain, for example, the portion to which the compound is distributed.

[0165] A method for generating a diagnostic image in a biological sample is also provided, comprising contacting the biological sample with an effective amount of a compound or imaging agent described herein, and generating an image related to the biological sample. In some embodiments, contacting and generation may be carried out in vitro. In some embodiments, contacting is in vivo and generation is in vitro.

[0166] A method is also provided for detecting the presence or absence of a pathological process associated with a protein prone to protein aggregation, such as huntingtin protein (HTT protein), in an individual, comprising: administering an effective amount of a compound or imaging agent described herein; generating an image and detecting the presence or absence of huntingtin protein (HTT protein) in the image; and detecting the presence or absence of a pathological process, such as a neurodegenerative disease. In some embodiments, the HTT protein exists as a monomer, oligomer, aggregate, or a combination thereof. In some embodiments, the protein prone to aggregation is huntingtin protein (HTT protein). The HTT protein may be a variant. 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 region is selected from the head, spinal cord, limbs, chest, and / or abdomen. In some embodiments, the body part or region is the brain. In some embodiments, the HTT protein is found in the basal ganglia. In some embodiments, the agglutinating protein, e.g., the HTT protein, is present in the brain, liver, heart, and / or muscles of an individual. In some embodiments, image generation includes 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 agglutinating protein, e.g., the HTT protein, is present in the basal ganglia, cortex, hippocampus, and / or brainstem of an individual's brain. In some embodiments, the agglutinating protein, e.g., the HTT protein, exists as monomers, oligomers, aggregates, or a combination thereof.

[0168] In some embodiments, individuals are found to have or be found to have Huntington's disease.

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

[0170] Diagnostic methods are also provided that use the compounds or imaging agents described herein to monitor disease progression in patients by quantifying changes in the levels of proteins prone to aggregation in those patients.

[0171] In some embodiments, compounds are provided that have a binding rate to protein aggregates suitable for functioning as imaging agents, such as HTT protein aggregates or β-amyloid protein aggregates. Thus, the compounds described herein can be characterized by one or more of: 1) high affinity for such protein aggregates; 2) low affinity for adjacent structures; and / or 3) slow dissociation rate from such protein aggregates. The dissociation rate can be represented as the dissociation rate constant k assn as defined by the following equation (where A and B refer to the protein aggregate and the imaging agent, and k diss is the binding rate constant). d[AB] / dt = k assn [A][B] - k diss [AB]

[0172] In some embodiments, an effective amount of the compounds or imaging agents described herein includes from about 0.1 to about 20 mCi. In some embodiments, an effective amount of the compounds or imaging agents described herein includes 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 values in the range between these. In some embodiments, an effective amount of the compounds or imaging agents described herein includes 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 At. 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 radionuclides selected from Br may be used. In specific applications, 99m The incorporation of chelated radionuclides such as Tc may also be useful. In some embodiments, 18 The longer half-life of F allows imaging to be performed for a sufficiently long time for a stronger signal to be generated, 18 F 11 C may be preferable to C. In some embodiments, the compounds or imaging agents described herein may be labeled with positron-emitting radionuclides or gamma-emitting radionuclides. Some examples of positron-emitting radionuclides include: 15 O, 13 N, 11 C, 18 F, 76 Br and 124 It contains I, which has 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 It may be labeled with a positron emitter selected from F. 11 The method for introducing C is, 11 C) Iodomethane or [ 11 This includes, but is not limited to, alkylation with [C]methyl triflate. Carbon 11 has a half-life of approximately 20 minutes, and therefore 11 C generally needs to be produced inside a cyclotron at the site, 11 [C]Can be produced as carbon dioxide. 11 [C] Carbon dioxide is a chemical species suitable for direct labeling (generally [ 11 The radiopharmaceuticals are converted to [C]iodomethane, etc., and after the appropriate radiochemical purity and specific activity are determined, the synthesis is completed in situ in PET imaging studies and used. 18Typical methods for introducing F include, but are not limited to, nucleophilic and electrophilic methods. Nucleophilic methods include substituting a halide, tosylate, or other leaving group with labeled cesium fluoride, potassium fluoride, tetrabutylammonium fluoride, tetramethylammonium fluoride, or potassium fluoride kryptofix-222. 18 Suitable electrophiles for introducing the [F] isotope 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]octanbis(tetrafluoroborate) (Selectfluor), N-fluoropyridinium triflate, xenon fluoride, 2-pyridinesulfonyl fluoride (PyFluor), 3-pyridinesulfonyl fluoride, 4-pyridinesulfonyl fluoride, 4-chloro-2-pyridinesulfonyl fluoride, ethensulfonyl fluoride, fluorobenzoiodoxol, 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 approximately 110 minutes, and therefore [ 18The synthesis of [Fluorine-18] radiopharmaceuticals does not necessarily need to be performed in a location with a cyclotron, nor does it need to be located near a PET imaging research center. Fluorine-18 is also expected to exhibit favorable nuclear and physical properties, including a high positron decay ratio (97%), a relatively short half-life (109.7 minutes), and a low positron energy (up to 0.635 MeV). This positron energy can correspond to a short in vivo diffusion range (<2.4 mm), which can provide an excellent resolution limit for PET images.

[0176] As will be recognized, the steps of the methods described herein do not need to be performed a specific number of times or in a specific order. Further objects, advantages and novel features of the present invention will become apparent to those skilled in the art in the description of the embodiments set forth below, 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 at least partially mediated by agglutinating proteins. In some embodiments, the compounds or imaging agents described herein are useful for treating diseases or conditions at least partially mediated by HTT proteins. In some embodiments, treatment of diseases or conditions at least partially mediated by agglutinating proteins may include administration of the compounds or imaging agents described herein. The treatment may include the co-administration of the compounds or imaging agents described herein with one or more other active agents and / or therapeutic agents. Accordingly, in some embodiments, a method is provided for treating or preventing a disease or condition at least partially mediated by agglutinating proteins in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compounds or imaging agents described herein.

[0178] Some embodiments provide a method for treating a disease or condition in a patient in need of such treatment that is at least partially mediated by a protein prone to aggregation, comprising administering to the patient a therapeutically effective amount of a compound of formula I', or an isotope-enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers thereof.

[0179] In some embodiments, a method for treating a disease or condition that is at least partially mediated by a protein prone to aggregation in a patient requiring the treatment, wherein the patient is given a therapeutically effective amount of Formula I; [A 1 is C; A 2 is C or N; A 3 CR 21 , NR 3 , or N; A 4 CR 22 , NR 3 , or N; A 5 CR 23 , NR 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 of these independently consists of hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C. 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy or C 3~6 It is a cycloalkyl; Each R 3 These are, independently, hydrogen and C 1~4 Alkyl, C 1~4 Haloalkyl, or C3~6 It is a cycloalkyl; A 6 CR 11 Or N, A 7 CR 12 Or N, A 8 CR 13 Or N, A 9 CR 14 Or N, A 6 , A 7 , A 8 , and A 9 Two or fewer of these are N; R 11 , R 12 , R 13 , and R 14 Each of these is hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 It is a haloalkoxy; X 1 is C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 It is an aryl, heteroaryl, or heterocyclyl, and X 1 1 to 4 R 4 It is sometimes replaced by; Each R 4 These are independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 It is a 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 It is an alkoxy; L is -(C(R 6 )2) m -where m is 1, 2, 3, or 4; Each R6 These are independently hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 It is a haloalkoxy, or two R 6 It can link with any intervening atom to form a 3-6 membered ring; L 1 is C(O), C(O)NR a , NR a C(O), or O, or L 1 It does not exist; R a is hydrogen, C 1~6 Alkyl, or C 1~6 It is a haloalkyl; L 2 These are 1 to 4 R's 7 C is sometimes replaced by 1~2 It is alkylene, or L 2 It does not exist; Each R 7 These are independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 [It is a haloalkoxy] A method is provided comprising administering a compound, optionally labeled with one or more radioactive isotopes, or an isotope-enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers.

[0180] Some embodiments provide a method for treating a disease or condition in a patient in need of such treatment that is at least partially mediated by a protein prone to aggregation, comprising administering to the patient a therapeutically effective amount of a compound selected from Table 1A or Table 1B, or an isotope-enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers thereof.

[0181] Examples of 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 mental 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 diseases in which elongated CAG repeat sequences result in long stretches of polyglutamine (polyQ) in the encoded protein. This group also includes dentatorubral-pallidoluysian atrophy (DRPLA), spinal medullary muscular atrophy (SBMA), and spinocerebellar ataxia (SCAs). In HD, selective neurodegeneration of gamma-aminobutyrate-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 multi-domain protein containing a polymorphic glutamine / proline-rich domain at its amino terminus. The IT encoding the HTT protein is also present. 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 elongation is inversely correlated with the age of disease onset, with early-onset cases characterized by more than 60 elongation repeats. Longer polyQ domains are thought to induce conformational changes in the HTT protein, which are thought to form intracellular aggregates, often appearing as nuclear inclusions. However, aggregates can also form outside the nucleus. The HTT protein is present in the nucleus, cell body, dendritic crystals, and nerve terminals of neurons and is 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. These basal ganglia organize the body's movements, or "motor activity," which are propelled by muscles. The main components of the basal ganglia are the caudate nucleus and putamen (commonly known together as the striatum) and the globus pallidus (external and internal regions). The substantia nigra and subthalamic nucleus are often also included as part of the basal ganglia.

[0185] The basal ganglia are a group of subcortical cell nuclei primarily responsible for motor control, as well as other roles such as motor learning, executive function and behavior, and emotion. Damage to the basal ganglia reticular tissue is thought to lead to several motor 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 striatal complex, and the excitability of medium spiny neurons is controlled by several presynaptic and postsynaptic mechanisms and interneuronal activity, and ensured by several recurrent or internal basal ganglia circuits. The motor circuits of the basal ganglia have two input points, the striatum and the subthalamic nucleus, and one output point, the globus pallidus internal segment, which connects to the cortex via the motor thalamus.

[0186] Administration of the compounds described herein may result in a reduction, for example, of at least 10% (e.g., at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 100%) of one or more symptoms of the diseases or conditions described herein. The diseases or conditions may be diseases, conditions, or disorders of the nervous system secondary to therapies that have a primary effect on areas other than the nervous system; damage to the nervous system caused by physical, mechanical, or chemical trauma; autoimmune neurodegeneration; neurodegeneration secondary to infection; and / or ocular neurodegeneration. Symptoms of neurodegeneration include, for example, tremors, bradykinesia, ataxia, balance disorders, depression, cognitive decline, short-term memory loss, long-term memory loss, confusion, personality changes, language problems, loss of sensation, sensitivity to touch, numbness in the limbs, muscle weakness, paralysis, muscle spasms, muscle cramps, marked 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 blind spots in vision, metamorphopsia, impaired color vision, reduced 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 the nervous system. Examples of neurodegenerative diseases include Alexander disease, Alpers disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia, Batten disease (also known as Spielmeiervojnt-Sjögren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Sträussler-Scheinker syndrome, Huntington's disease, dementia associated with HIV, Kennedy disease, and Krabbe disease. These include Kuru, Lewy body dementia, Machad-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 degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia, spinal muscular atrophy, Steele-Richardson-Olsewski 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 and bulbar muscular atrophy, spinocerebellar ataxia, spinal cord and / or brain injury, chronic pulmonary hypertension, Parkinson's disease, amyotrophic lateral sclerosis, cavernous hemangioma, cardiovascular disease, Alzheimer's disease (AD), glaucoma, multiple sclerosis (MS), corneal lesions, diabetes mellitus, chronic and / or neuropathic pain, stroke, ischemia, retinal disease, spinal muscular atrophy (SMA), erectile dysfunction, (non-hypertensive) nephropathy, hypertensive nephropathy, hypertension, optic nerve injury, hepatic fibrosis, lupus, post-transplant liver failure, encephalomyelitis, epilepsy, and neurogliablastoma.

[0189] The compounds described herein, when administered to a subject, may inhibit neuronal degeneration. In some embodiments, inhibiting neuronal degeneration may include inhibiting the degeneration of axons or neurons in neurons. Such inhibition may affect all neurons or parts thereof, for example, neuronal cell bodies, axons, and dendrites. This can be evaluated, for example, by analysis of nervous system function by methods known in the art. Administration of the compounds described herein may result in a reduction of at least 10% (e.g., at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%) of the number of degenerating neurons (or their neuronal bodies, axons, or dendrites) in a neuronal population or subject compared to the number of degenerating neurons (or their neuronal bodies, axons, or dendrites) in a neuronal population or subject that has not been administered one or more of the compounds described herein.

[0190] Neurons can transmit information from tissues and organs to the central nervous system (afferent or sensory neurons) and 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 specific examples of neuronal types that may be targeted for treatment by this 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 targeted for treatment by this disclosure include astrocytes and microglia.

[0191] Furthermore, the compounds described herein can be used to prevent or treat memory loss. Types of memory affected by loss and thus treatable by this 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 and bulbar muscular atrophy, spinocerebellar ataxia, spinal cord and / or brain injury, chronic pulmonary hypertension, Parkinson's disease, amyotrophic lateral sclerosis, cavernous hemangioma, cardiovascular disease, Alzheimer's disease (AD), glaucoma, multiple sclerosis (MS), corneal lesions, diabetes mellitus, chronic and / or neuropathic pain, stroke, ischemia, retinal disease, spinal muscular atrophy (SMA), erectile dysfunction, (non-hypertensive) nephropathy, hypertensive nephropathy, hypertension, optic nerve injury, hepatic fibrosis, lupus, post-transplant hepatic failure, encephalomyelitis, epilepsy, and neurogliablastoma. In some embodiments, the pathological process is a neurodegenerative disease selected from Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, prion disease, and spinocerebellar ataxia. In some embodiments, the neurodegenerative disease is classified as a triplet repeat disease. In some embodiments, the triplet repeat disease is classified as belonging to Category I, Category II, or Category III.

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

[0195] The use of the compounds described herein for the manufacture of pharmaceuticals for use in the diagnosis, prevention, or treatment of the diseases or conditions described herein is also provided. For example, the disease or condition may be Huntington's disease.

[0196] Imaging agents and pharmaceutical compositions Imaging agents generally include compounds described herein that are labeled with positron-emitting radionuclides. Due to the short half-life of the radionuclides, positron-emitting radionuclides are typically administered intravenously immediately (e.g., within one hour of synthesis). The required amount of imaging agent is usually determined by the prescribing physician. Dosages can vary, but are not limited to, the binding rate of the compound, the amount emitted from the radionuclides used, the half-life of the radionuclides, the body part, area, and / or tissue to be imaged, and individual characteristics. Those skilled in the art will understand that an effective dose is generally 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 dose of imaging agent may be about 0.1 to about 500 mg.

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

[0198] With regard to PET imaging, the administration of the compounds or imaging agents described herein to an individual may be intravenous. The pharmaceutical compositions may be in the form of sterile, injectable aqueous or oily suspensions. These suspensions may be formulated according to known techniques using these preferred dispersants or wetting agents and suspensions listed herein. Sterile injectable products may also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable vehicles, such as solutions in 1,3-butanediol. Acceptable vehicles that may be used include water, Ringer's solution, and isotonic sodium chloride solutions. In addition, sterile, non-volatile oils have been used in the prior art as solvents or suspension media. For this purpose, any non-irritating non-volatile oil, including synthetic mono and diglycerides, may be used. In addition, fatty acids such as oleic acid may be useful in the preparation of injectable products. Such solutions may be formulated with appropriate salts in 0.01% to 10% isotonic solutions, pH 5 to 7.

[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 drip 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 buffers may 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] A pharmaceutical composition, such as a pharmaceutical composition for injection, may contain cyclodextrin. The cyclodextrin may be, for example, hydroxypropyl cyclodextrin or sulfobutyl ether cyclodextrin. The cyclodextrin may be, for example, α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin.

[0201] The compounds or imaging agents described herein may be administered via sustained-release formulations placed in specific tissues, including microspheres, liposomes, other particulate delivery systems, or blood. Suitable examples of sustained-release carriers include common products, such as semipermeable polymer matrices in the form of suppositories or microcapsules. Examples of the techniques or protocols described above and other techniques or protocols that may 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 full contents of which are incorporated herein by reference.

[0202] In some embodiments, the compounds or imaging agents described herein are administered as a pharmaceutical composition. Thus, a pharmaceutical composition comprising at least one compound or imaging agent described herein is provided, 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] Pharmacopoeia-acceptable vehicles must be sufficiently pure and sufficiently toxic to be suitable for administration to the animal being treated. Vehicles may be inactive, or they may have pharmaceutically beneficial properties. The amount of vehicle used with the compound or imaging agent may be sufficient to provide a practical amount of material for each dose of the compound or imaging agent.

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

[0205] An active agent may be included in the pharmaceutical composition, which does not substantially interfere with the activity of the compound or imaging agent described herein.

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

[0207] When the compounds or imaging agents described herein are mixed or added, the resulting mixture may be a solution, suspension, emulsion, etc. The form of the resulting mixture depends on many factors, including the intended administration method and the solubility of the compound or imaging agent in the selected vehicle. An effective concentration sufficient for imaging or therapy can be experimentally determined by methods known in the art.

[0208] Pharmaceutical compositions may be formulated for oral use, for example, as tablets, 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, fragrances, colorants and preservatives, to provide a simple and palatable pharmaceutical product. In some embodiments, the oral pharmaceutical composition contains 0.1 to 99% of the compounds or imaging agents described herein. In some embodiments, the oral pharmaceutical composition contains at least 5% (by weight) of the compounds or imaging agents. Some embodiments contain 25% to 50% or 5% to 75% of the compounds or imaging agents.

[0209] Pharmaceutical compositions administered orally may also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups, and the like. Suitable pharmaceutically acceptable carriers for the preparation of such compositions are well known in the art. Oral pharmaceutical compositions may contain preservatives, fragrances, sweeteners such as sucrose or saccharin, taste masking agents, and colorants.

[0210] Typical components of carriers for syrups, elixirs, emulsions, and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. The syrups and elixirs may also be formulated with sweeteners, such as glycerol, propylene glycol, sorbitol, or sucrose. Such pharmaceutical compositions may also contain mitigating agents.

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

[0212] Typical suspending agents for suspensions include methylcellulose, sodium carboxymethylcellulose, Avicel® RC-591, tragacanth, and sodium alginate; typical humectants include lecithin and polysorbate 80; and typical preservatives include methylparaben and sodium benzoate.

[0213] Aqueous suspensions containing a compound or imaging agent in a mixture with an excipient suitable for the production of aqueous suspensions are provided. Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum, and the dispersing or wetting agent may be a naturally occurring phosphatide, such as lecithin, or a condensation product of alkylene oxide with a fatty acid, such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long-chain aliphatic alcohol, such as heptadecaethyleneoxycetanol, or a condensation product of ethylene oxide with a fatty acid and a partial ester derived from hexitol, such as polyethylene sorbitol substituted derivatives, or a condensation product of ethylene oxide with a fatty acid and a partial ester derived from hexitol anhydride, such as polyethylene sorbitan substituted derivatives. The aqueous suspension may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate.

[0214] Oily suspensions can be formulated by suspending a 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. The oily suspension may contain thickeners, such as beeswax, solid paraffin, or cetyl alcohol. Sweeteners and flavorings, such as those mentioned above, may be added to provide a palatable oral product. These pharmaceutical compositions may be preserved by adding antioxidants 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 rubbers, such as acacia rubber or tragacanth rubber, naturally occurring phosphatides, such as soy, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, such as sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, such as sorbitan polyethylene monooleate.

[0216] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide the active ingredient in an additive mixture with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are illustrated by those already listed above.

[0217] Tablets typically contain, as inert diluents, pharmaceutically acceptable adjuvants of the prior art, 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, may be used to improve the flow properties of powder mixtures. Colorants, such as FD&C dyes, may be added for appearance. Sweeteners and flavorings, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, may be useful adjuvants for chewable tablets. Capsules (including time-release and sustained-release formulations) typically contain one or more solid diluents disclosed above. The selection of carrier components is often based on secondary considerations such as taste, cost, and storage stability.

[0218] The pharmaceutical composition may be coated by conventional methods, typically by pH or time-dependent coatings, so that the compound or imaging agent is released into the gastrointestinal tract near the desired topical application or at various rates to extend the desired effect. Such dosage forms typically include, but are not limited to, one or more cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethylcellulose, Eudragit® coatings, waxes, and shellac.

[0219] Pharmaceutical compositions for oral use may also be provided as hard gelatin capsules, where the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules, where the active ingredient is mixed with water or an oily 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 thus melts in the rectum to release the drug. Examples of 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 the eyes, in the form of gels, creams and lotions, and for application to the eyes. 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 its isotopically labeled analogues, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers or mixtures of stereoisomers, or imaging agents described herein, may be mixed with various carrier materials well known in the art, such as water, alcohol, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, myristyl PPG-2 propionate, etc.

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

[0224] Typical softening agents include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecane-2-ol, isocetyl alcohol, cetyl palmitate, 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, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate and myristyl myristate; sprays, e.g., propane, porcine Examples include isobutane, dimethyl ether, carbon dioxide and nitrous oxide; 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, and 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, rubber, colloidal silicon dioxide, sodium polyacrylate, tetraalkylammonium smectite, trialkylarylammonium smectite, chemically modified aluminum magnesium 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 transdermal patches.

[0226] The compounds or imaging agents described herein may also be administered via liposome delivery systems. Liposomes can be classified into small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. Liposomes can be formed from various amphiphilic molecules, particularly phospholipids. Examples of liposome components include cholesterol, stearylamine, and / or phosphatidylcholine. Liposomes are suitable for various administration routes, including local and intra-tissue injection. Therefore, intravitreous (e.g., in the treatment of glaucoma), intraperitoneal, intravenous, intravascular, intra-articular, and intramuscular administration of liposomes is possible.

[0227] Other pharmaceutical compositions useful for achieving systemic delivery of compounds or imaging agents include sublingual, intraoral, and nasal administration 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 lubricants, oils, sweeteners, colorants, antioxidants, and fragrances disclosed above may also be included.

[0228] Pharmaceutical compositions for inhalation can typically be provided in the form of solutions, suspensions, or emulsions, and may be administered as dry powders or in the form of aerosols using conventional sprays (e.g., dichlorodifluoromethane or trichlorofluoromethane).

[0229] The pharmaceutical composition may optionally contain an activity enhancer. The activity enhancer can be selected from a wide variety of molecules that function in various ways, either enhancing or not relying on, the therapeutic effect of the compounds or imaging agents described herein. Certain classes of activity enhancers include skin penetration enhancers and absorption enhancers.

[0230] The pharmaceutical composition may contain additional active agents, which can 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. Any of these other active agents, when present, are typically utilized in the pharmaceutical composition at levels ranging from 0.01% to 15%. In some embodiments, they constitute 0.1% to 10% by weight of the composition. In other embodiments, they constitute 0.5% to 5% by weight of the composition.

[0231] The dosage of the compounds or imaging agents described herein depends on a variety of factors, including the specific pathological process being treated or detected, the individual's physiology, the severity of the symptoms, the route of administration, the frequency of the dosing interval, the specific compound used, the efficacy of the compound, its toxicological profile, pharmacokinetic profile, and the presence of toxic side effects, as well as other considerations. The dosage under specific circumstances should be determined appropriately by the practitioner based on the above and other factors.

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

[0233] Kit and packaging Kits comprising the compounds or imaging agents described herein and appropriate packaging are also provided herein. In certain embodiments, the kit further includes instructions for use. In some embodiments, the kit includes the compounds or imaging agents described herein and labels and / or instructions for the use of the compounds in the treatment of indications including the diseases or conditions described herein.

[0234] A manufactured article containing the compounds or imaging agents described herein in a suitable container is also provided herein. The container may be a vial, bottle, ampoule, pre-filled syringe, or intravenous bag.

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

[0236] In all the preceding descriptions, the compound or imaging agent may be administered alone, as a mixture, or in combination with other active agents.

[0237] The use of compounds or imaging agents described herein for the manufacture of pharmaceuticals for use in the diagnosis, prevention, or treatment of diseases or conditions described herein is also provided. For example, the disease or condition may be Huntington's disease.

[0238] The use of the compounds described herein for the manufacture of imaging agents for use in the diagnosis, prevention, or treatment of the diseases or conditions described herein is also provided. For example, the disease or condition may be Huntington's disease.

[0239] Combination therapy The methods described herein include methods for detecting, treating or preventing diseases or conditions described herein, comprising administering a compound or imaging agent described herein and one or more additional active agents to a subject 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 administered separately. When used in combination with one or more additional active agents, the compounds or imaging agents described herein may be administered before, simultaneously with, or after the administration of the additional active agents. The administration may be via the same route or different routes.

[0240] Pharmaceutical compositions are also provided that include the compounds or imaging agents described herein and one or more additional active agents used in the treatment of Huntington's disease, for example, 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. Similarly, also provided are pharmaceutical compositions comprising compounds or imaging agents described herein, and packaged pharmaceutical compositions comprising another composition comprising one or more additional active agents used for the treatment of Huntington's disease, for example, 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] Methods for treating or preventing Alzheimer's disease, including memory and / or cognitive impairment associated with Alzheimer's disease, are also provided, comprising administering the compounds or imaging agents described herein and one or more additional agents to a subject simultaneously or sequentially. In some embodiments, the active agent is Reminyl® (galantamine), Cognex® (tacrine), Aricept® (donepezil), Exelon® (rivastigmine), Akatinol® (memantine), Neotropin® (somatropin), Eldepryl® (selegiline), estrogen, or cryoquinol.

[0242] In some embodiments, the compounds described herein can be administered together with active agents for treating Parkinson's disease, for example, L-dopa, dopamine agonists (e.g., bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphine, and rislide), 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 together with active agents for treating Alzheimer's disease, for example, acetylcholinesterase inhibitors (e.g., donepezil, galantamine, and rivastigmine), and / or NMDA receptor antagonists (e.g., memantine).

[0243] Compound synthesis The compounds or imaging agents described herein may be prepared using the methods disclosed herein and their usual modifications as evident from the disclosure herein and from methods well known in the art. Conventional and well known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein may be achieved as described in the following examples. Where available, reagents may be purchased commercially from, for example, 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 temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it is understood that other process conditions may also be used unless otherwise stated. Optimal reaction conditions may vary depending on the specific reactants or solvent used, but such conditions can be determined by those skilled in the art through standard optimization procedures.

[0245] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting specific 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] Furthermore, the compounds or imaging agents described herein may contain one or more chiral centers. Thereafter, if desired, such compounds may be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included in the scope of the present invention unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds may be separated, for example, using chiral column chromatography, supercritical fluid chromatography, chiral resolving agents, etc. If pure or enriched compounds as enantiomers are desired, chiral chromatography and / or pure or enriched starting materials as enantiomers may 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 suppliers such as Sigma Aldrich and Alfa Aesar. Others can be prepared by procedures or obvious modifications thereof described in standard references such as Fieser and Fieser's Reagents for Organic Synthesis, Vol. 1–15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Vol. 1–5 and Supplement (Elsevier Science Publishers, 1989), Organic Reactions, Vol. 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 solvents that are inert under the conditions of the reaction described therein (e.g., benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine, etc.). Generally, when the term inert is used herein with respect to a solvent, it refers to a material that does not form the target compound of interest, even if the reaction is one in which carbon-carbon bonds are formed. Unless otherwise specified, the solvents used in the reactions of this 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 sufficient amount to achieve the stated function, for example, to bring the solution to the desired volume (i.e., 100%).

[0250] It is also understood that the addition of any substituent in each of the following schemes may result in the generation of numerous isomeric products (including, but not limited to, enantiomers or one or more diastereomers) of which any or all can be isolated and purified using conventional techniques.

[0251] The incorporation of labels into the compounds or imaging agents described herein may be carried out by reacting a suitable starting material with a reagent containing a radioisotope. The method generally follows the same principles as standard organic chemical reactions and can be carried out by any method known to those skilled in the art, including those provided herein.

[0252] Scheme 1 provides an exemplary synthetic route for the synthesis of the 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 typically prepared by first preparing a 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 , ring Z, and X 2 This is as defined herein; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 51It is defined as follows:

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

[0256] Compound Vf can be synthesized from compound Ve in one or more steps. In compound Vf, Z 5 Ha-LL 1 -L 2 -X 1 or derivatives, for example, a protected derivative or isotope-enriched analog thereof, or Z 5 These are LN(PG)2, L-NH(PG), L-NH2, or LC(O)Z 6 (wherein the formula, PG is a suitable amine protecting group (e.g., benzyl, tert-butoxycarbonyl, or benzyloxycarbonyl, or two PGs forming phthalimide).) For example, Z 5 In X 1 The hydroxyl group above may be protected with a typical hydroxyl protecting group (e.g., benzyl). In compound Ve, Z 51 is Z 5 Or it is H. Z 5 is L-NH2 or LC(O)Z 6 If L 1 -L 2 -X 1 The amide bond may be added by an amide bond formation reaction (for example, a coupling agent, e.g., HATU, CDI, or T3P, and a base, e.g., triethylamine, diisopropylethylamine, or piperidine, or other conditions known in the art). 5 If it is LN(PG)2 or L-NH(PG), amine deprotection can be carried out under standard conditions. 51 If it is H, then -LL 1 -L 2 -X 1 This includes, for example, nucleophilic substitution reactions (e.g., a base, e.g., K2CO3, NaH or NaOH, and 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, p-toluenesulfonate, or as another method, Z 5 -Z 6 The addition may be carried out by a conjugate addition substrate, for example, an α,β unsaturated carbonyl (including alkylpropa-2-enoate, for example, ethylpropa-2-enoate). 5 -Z 6 If the compound contains an ester, hydrolysis can be carried out under the conditions described herein or known in the art (e.g., a solvent containing water, e.g., LiOH, NaOH, or KOH in 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. Compound Vc or compound Vd can be synthesized from compound Va and compound Vb, if necessary.

[0258] Z 3 and Z 4 Z is a suitable group for the formation of aryl-aryl bonds. For example, Z 3 The leaving group may be a fluoro or pseudohalide, such as a sulfonyl (e.g., mesyl), and the synthesis may be, for example, Z 3 and Z 4 The reaction proceeds via a nucleophilic addition reaction or aryl coupling reaction between the two. For example, Z 4 A may be a hydrogen atom, and nucleophilic aromatic substitution is A 21 A nucleophilic center is added to the appropriate leaving group Z. 3 The reaction proceeds by substituting (e.g., fluoride or nitro), and the reaction conditions include a suitable inert solvent (e.g., a polar aprotic solvent, e.g., DMF or acetonitrile) and a high temperature (e.g., 50-200°C), possibly in the presence of a base (e.g., NaH or Cs2CO3).

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

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

[0261] Alternatively, Z 1 Z is a leaving group, which may be a fluoro or nitro group, and is used in nucleophilic addition or aryl coupling reactions. 1 and Z 2 This can be done between Z. 2 If it contains a nucleophilic center (for example, Z 2 If is -C(O)NH(PG), Z 2 For example, Z 2 In the amide nitrogen atom, Z 1 It may undergo nucleophilic substitution.

[0262] In some embodiments, Z 1 It is nitro. Z 1 If it is nitro, then Z 1 It may be reduced under appropriate conditions, for example, using sodium dithionite, an iron metal and an acid (e.g., acetic acid), or trichlorosilane. In some embodiments, Z1 Nitro reduction and Z 1 Z in 2 Bond formation to Z can be carried out in a one-pot reaction. Alternatively, 1 If it is nitro, then Z 1 Z can act as a leaving group in nucleophilic substitutions. In some embodiments, Z 1 The compound Vd is a nitro group, and the synthesis proceeds via compound Vd by exposing compound Vd to reducing and cyclization conditions containing 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 of 0-150°C.

[0263] In some embodiments, Z 1 Z in 2 Reaction to and Z 3 Z in 4 The reaction can occur in a single pot, in which case it is not necessary to isolate either compound Vc or compound Vd.

[0264] Those skilled in the art will understand that any of the compounds Va, Vb, Vc, Vd, Ve, or Vf may be available from suppliers for specific embodiments. Alternative synthesis of compounds Va, Vb, Vc, Vd, Ve, or Vf may be as described herein or known to those skilled in the art. [Examples]

[0265] The following embodiments are included to demonstrate specific embodiments of the present invention. Those skilled in the art will understand that the techniques disclosed in the subsequent embodiments represent techniques that function well in carrying out the present invention and may thus be considered to constitute a specific mode for its implementation. However, those skilled in the art will understand that numerous modifications may be made to the specific embodiments disclosed, and similar results can be achieved without departing from the spirit and scope of the present invention.

[0266] 1. General experimental procedure Commercially available reagents and solvents (HPLC grade) were used without further purification. Spectrometers were used in deuterium solvent with a Bruker DRX 500 MHz spectrometer, a Bruker DPX 250 MHz spectrometer, a Bruker AVANCE 300, or a Bruker AVANCE 500 spectrometer. 1 ¹H NMR spectra were recorded. Chemical shifts (δ) are expressed in parts per million. Flash column chromatography refers to automated purification using a Biotage Isolera system with 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, where the sample was placed in methanol and eluted with methanol, then with 5% ammonia in methanol.

[0267] 2.Analysis method Acid phase HPLC method Analytical HPLC-MS (METCR1673) was performed using a Shimadzu LCMS-2010EV system with a Supelco Ascentis Express reverse-phase column (2.7 μm, 2.1 × 30 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 1.5 minutes, followed by 100% B for 0.1 minutes, 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 obtained using the LCMS2010EV at a sampling rate of 2 scans per second, over the range of m / z 100–1000. Data were integrated and reports were generated using Shimadzu LCMS-Solutions and PsiPort software.

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

[0269] Alternatively, analytical HPLC-MS (METCR1416) was performed using a Shimadzu LCMS-2010EV system with a Waters Atlantis dC18 reversed-phase column (3 μm, 2.1 × 100 mm), with a gradient of 5 to 100% B (A = water / 0.1% formic acid, B = acetonitrile / 0.1% formic acid), at a column temperature of 40°C for 5.0 minutes, followed by 100% B for 0.4 minutes, with an injection volume of 3 μL and a flow rate of 0.6 mL / min. The UV spectrum was recorded at 215 nm using an SPD-M20A PDA detector. Mass spectra were obtained using the LCMS2010EV at a sampling rate of 2 scans per second, in the range of m / z 100 to 1000. The data were integrated and a report was generated using Shimadzu LCMS-Solutions and PsiPort software.

[0270] Alternatively, analytical HPLC-MS (MET-uHPLC-AB-101) was performed using a Waters Acquity UPLC system equipped with Waters PDA and ELS detectors, with a Phenomenex Kinetex-XB C-18 column (1.7 μm, 2.1 mm × 100 mm). The procedure involved 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 5.3 minutes, followed by 100% B for 0.5 minutes, 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 obtained using a Waters ZQ at a sampling rate of two scans per second, over the range of m / z 150–850. Data were integrated and reports were generated using OpenLynx software.

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

[0272] [Table 4]

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

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

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

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

[0277] Basic phase HPLC method Analytical HPLC-MS (METCR0990) was performed using a Hewlett Packard HPLC system with a Phenomenex Gemini C18 reversed-phase column (3 μm, 2.0 × 50 mm) at a column temperature of 60°C. The procedure involved a gradient of 1–100% B (A = 2 mM ammonium bicarbonate buffered in pH 10 water, B = acetonitrile) for 1.8 minutes, followed by 100% B for 0.3 minutes, 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 obtained using a Waters ZQ at a sampling rate of two scans per second, covering the range of m / z 150–850. Data were integrated and reports were generated using OpenLynx software.

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

[0279] Subsequently, the METCR1600 method was replaced with the METCR1603 method, and the flow rate was increased to 0.6 mL / min. All other parameters remained unchanged.

[0280] Alternatively, analytical HPLC-MS (MET-uHPLC-AB-102) was performed using a Waters Acquity UPLC system equipped with Waters PDA and ELS detectors, employing a Waters UPLC® CSH® column (1.7 μm, 2.1 × 100 mm), at a column temperature of 40°C. The procedure involved a gradient of 5–100% B (A = 2 mM ammonium bicarbonate buffered in pH 10 water, B = acetonitrile) for 5.3 minutes, followed by 100% B for 0.5 minutes, 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 obtained using a Waters Quattro Premier XE at a sampling rate of two scans per second, covering the range of m / z 150–850. Data were integrated and reports were generated using OpenLynx software.

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

[0282] Method 1 Scheme of Method 1

[0283] [ka]

[0284] [Example 1-1] Step 1: 5-{4-[(2R,6R)-2,6-dimethylmorpholine-4-yl]-4-oxobutyl}-7-fluoro-4H,5H-pyrrolo[1,2-a]quinoxaline-4-one 4-(7-fluoro-4-oxo-pyrrolo[1,2-a]quinoxaline-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 organic matter was dried and concentrated in (MgSO4). Further purification by basic preparative HPLC yielded 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 were also prepared using this route:

[0286] [Table 5] TIFF2026053514000040.tif227150TIFF2026053514000041.tif239150TIFF2026053514000042.tif240150TIFF2026053514000043.tif239150 TIFF2026053514000044.tif239149TIFF2026053514000045.tif233150TIFF2026053514000046.tif220149TIFF2026053514000047.tif219150 TIFF2026053514000048.tif239151TIFF2026053514000049.tif239150TIFF2026053514000050.tif239150TIFF2026053514000051.tif239150 TIFF2026053514000052.tif239150TIFF2026053514000053.tif239150TIFF2026053514000054.tif239150TIFF2026053514000055.tif111151

[0287] Method 2 Scheme of Method 2

[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-nitropyridine (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 ground with water (50 mL) to obtain 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).Tr(METCR1410) = 1.05 min, (ES + ) (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-pentaene-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. Sodium dithionite (1.97 g, 11.3 mmol) was added, and the reaction was stirred overnight at room temperature. The mixture was concentrated under vacuum to approximately 30 mL, diluted with water (10 mL), and filtered. The solid was dried overnight under vacuum to obtain 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) in anhydrous DMF (5 mL) 2,8,11-triazatricyclo[7.4.0.0 2,6 The compound was gradually added over 5 minutes to a cold (0°C) solution of trideca-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 warmed to room temperature and stirred for 7 hours. The reaction mixture was concentrated to dryness and ground with water (50 mL). The compound was purified by column chromatography (10-60% ethyl acetate in silica and heptane) to obtain 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 2,6Trideca-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. The precipitate was ground with methanol (2 mL) to obtain 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), HATU (63 mg, 0.166 mmol), 4-(7-oxo-2,8,11-triazatricyclo[7.4.0.0 2,6 The compound was treated with a solution of 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. The compound was purified by basic preparative HPLC to obtain 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 were also prepared using this route:

[0295] [Table 6] TIFF2026053514000058.tif84149

[0296] Method 3 Scheme of Method 3

[0297] [ka]

[0298] [Example 3-1] Step 1: Methyl 1-(4-fluoro-2-nitrophenyl)pyrrole-2-carboxylate Methyl 1H-pyrrole-2-carboxylate (5.00 g, 40.0 mmol) and Cs2CO3 (14.47 g, 44.4 mmol) were dissolved in DMF (10 mL), and 1,4-difluoro-2-nitrobenzene (7.06 g, 44.4 mmol) was added. The reaction mixture was heated overnight at 60°C. Cs2CO3 (2.05 g, 6.29 mmol) was added, and the reaction mixture was heated at 60°C for 2 hours. The reaction mixture was concentrated. The residue was partitioned between water (100 mL) and pharmaceutically acceptable ethyl acetate (100 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic matter was dried (MgSO4) and concentrated under vacuum. It was ground with MeCN (20 mL) to obtain 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-nitrophenyl)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 at 100°C for 30 minutes. The mixture was concentrated under vacuum, and the residue was stirred in methanol (100 mL) at 80°C for 30 minutes. The slurry was filtered through Celite while washing with another portion (100 mL) of hot methanol. The combined filtrate was concentrated under vacuum to obtain 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]quinoxaline-5-yl)propanoate 7-Fluoro-5H-pyrrolo[1,2-a]quinoxarin-4-one (700 mg, 3.46 mmol) was suspended in THF (40 mL), and then ethylpropane-2-enoate (1.8 mL, 17.3 mmol) and sodium hydroxide (692 mg, 17.3 mmol) were added. The mixture was stirred at room temperature for 4 days. 2N HCl (25 mL) was slowly added to acidify the mixture, and the turbid white mixture was extracted with DCM (3 × 100 mL). The combined organic layers were dried (MgSO4) and concentrated under vacuum. The crude material was ground with methanol (5 mL), dried on a filter, and the title compound was obtained. 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-(piperidine-1-yl)propyl]-4H,5H-pyrrolo[1,2-a]quinoxaline-4-one 3-(7-fluoro-4-oxo-pyrrolo[1,2-a]quinoxaline-5-yl)propanoic acid (80 mg, 0.3 mmol) was dissolved in DMF (2 mL), then piperidine (89 μL, 0.9 mmol) was added, followed by 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 obtain 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 were also prepared using this route:

[0303] [Table 7] TIFF2026053514000061.tif232149TIFF2026053514000062.tif232150TIFF2026053514000063.tif23 9151TIFF2026053514000064.tif239150TIFF2026053514000065.tif240151TIFF2026053514000066.t if227151TIFF2026053514000067.tif239151TIFF2026053514000068.tif228150TIFF20260535140000 69.tif240150TIFF2026053514000070.tif240150TIFF2026053514000071.tif240150TIFF20260535140 00072.tif240150TIFF2026053514000073.tif240150TIFF2026053514000074.tif240150TIFF2026053 514000075.tif222150TIFF2026053514000076.tif222150TIFF2026053514000077.tif222150TIFF202 6053514000078.tif234150TIFF2026053514000079.tif234150TIFF2026053514000080.tif234150TIF F2026053514000081.tif242150TIFF2026053514000082.tif241151TIFF2026053514000083.tif126151

[0304] Method 4 Scheme of Method 4

[0305] [ka]

[0306] [Example 4-1] Step 1: Method 3 was carried out as in Step 1. Step 2: 2,8,13-Triazatricyclo[7.4.0.0 2,6]trideca-1(9),3,5,10,12-pentaene-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 mixture was diluted with DCM (40 mL) and slowly added to saturated aqueous NaHCO3 (50 mL) [Note: Significant gas generation occurred, and the reaction mixture became very foamy]. The mixture was stirred at room temperature for 30 minutes, then separated and extracted with DCM (2 × 25 mL). The combined organic matter was dried (MgSO4), concentrated to dryness, and obtained methyl 1-(3-amino-2-pyridyl)pyrrole-2-carboxylate. This was used 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 at 100°C for 30 minutes. The reaction mixture was concentrated to dryness and ground with water (2 mL) to obtain 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: Method 2 was implemented as described in Steps 3-5.

[0309] The following were also prepared using this route:

[0310] [Table 8] TIFF2026053514000086.tif240149TIFF2026053514000087.tif239150TIFF2026053514000088.tif239149TIFF2026053514000089.tif25149

[0311] Method 5 Scheme of Method 5

[0312] [ka]

[0313] [Example 5-1] Step 1: Method 3 was carried out as in Step 1. Step 2: 4H,5H-pyrolo[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 cooled to room temperature and concentrated under reduced pressure. 1N HCl (250 mL) was slowly added to the residue. Unreacted iron powder was collected using a magnetic rod, 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 overnight under vacuum. 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 obtain 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: Method 2 was implemented as described in Steps 3-5. The following were also prepared using this route:

[0315] [Table 9] TIFF2026053514000092.tif222150TIFF2026053514000093.tif240149TIFF2026053514000094.tif240149 TIFF2026053514000095.tif240149TIFF2026053514000096.tif227151TIFF2026053514000097.tif207150

[0316] Method 6 Scheme of Method 6

[0317] [ka]

[0318] [Example 6-1] Step 1: Method 2 was carried out as in Step 1. Step 2: 2,8,12-Triazatricyclo[7.4.0.0 2,6 ]trideca-1(9),3,5,10,12-pentaene-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 under vacuum, and the resulting aqueous solution was basicized to pH 8 with saturated aqueous solution NaHCO3. The solution was extracted with siRNA (4 × 30 mL), the combined organic matter was dried to (Na2SO4), filtered, and concentrated under vacuum to obtain 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: Method 2 was implemented as described in Steps 3-5. The following were also prepared using this route:

[0320] [Table 10] TIFF2026053514000100.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]quinoxaline-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 overnight at 60°C. 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 obtain 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: Implemented as described in Method 3, Steps 3-4. The following were also prepared using 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, the filtrate was diluted with water, extracted with DCM (3×), dried (MgSO4), and concentrated to dryness. The product was dried under vacuum at 40°C to obtain the title compound. It 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 mixture was heated at 150°C for 48 hours. A further portion of sodium hydride (1 equivalent) was added, and heating was continued at 150°C for a further 24 hours. The reaction mixture was poured into an ammonium chloride solution, the resulting precipitate was isolated by filtration, washed with water, and dried under vacuum to obtain the title compound. 1 ¹H NMR (500 MHz, chloroform-d) δ values: 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]quinoxaline-5-yl}propanoate 7-Fluoro-4H,5H-pyrazolo[1,5-a]quinoxarin-4-one (126 mg, 0.620 mmol) was dissolved in THF (6 mL) in a sealed tube, sodium hydroxide (149 mg, 3.72 mmol) was added, followed by ethylpropane-2-enoate (0.33 mL, 3.10 mmol). The mixture was stirred at 60°C for 72 hours. 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 solution was extracted to ELISA (3×), dried, and concentrated to obtain 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]quinoxaline-5-yl}-N-(5-methoxypyridine-2-yl)propanamide 3-(7-fluoro-4-oxo-pyrazolo[1,5-a]quinoxaline-5-yl)propanoic acid (100 mg, 0.182 mmol) was dissolved in DMF (1.5 mL), and then 5-methoxypyridine-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 mixture was stirred at room temperature for 7 hours. The reaction mixture was purified by basic preparative HPLC to obtain 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 were also prepared using this route:

[0333] [Table 12] TIFF2026053514000105.tif240149TIFF2026053514000106.tif227149TIFF2026053514000107.tif219150

[0334] Method 9 Scheme of Method 9

[0335] [ka]

[0336] [Example 9-1] Step 1: (E)-3-(dimethylamino)-1-(4-fluoro-2-nitrophenyl)propa-2-en-1-one 1-(4-fluoro-2-nitrophenyl)ethanone (300 mg, 1.64 mmol) was dissolved in 1,1-dimethoxy-N,N-dimethylmethaneamine (2.2 mL, 16.4 mmol) in a sealed tube, and the reaction mixture was heated at 90°C for 3 hours. The reaction mixture was concentrated under vacuum to obtain 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-nitrophenyl)-1-methylpyrazole Under a nitrogen atmosphere, methylhydrazine (0.19 mL, 3.58 mmol) was added in a pressure tube to a solution of (E)-3-(dimethylamino)-1-(4-fluoro-2-nitrophenyl)propa-2-en-1-one (310 mg, 1.30 mmol) in acetic acid (3.1 mL). The mixture was stirred at room temperature for 4 hours. The reaction liquid was poured into a water / ethyl acetate mixture. The aqueous layer was separated, and the organic layer was washed with water and brine, then dried to (MgSO4). The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica, n-hexane / ethyl acetate) to obtain 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-nitrophenyl)-1-methylpyrazole 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-methylpyrazole-3-yl)aniline 5-(4-fluoro-2-nitrophenyl)-1-methylpyrazole (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 in a sealed tube at 60°C for 5 hours. The crude product mixture was concentrated under vacuum, and the residue was stirred for 1 hour in a mixture of 1 M Na2CO3 (100 ml) and siRNA (100 ml). The mixture was then filtered through fiberglass filter paper. The filtrate was separated, and the aqueous layer was extracted with siRNA (2 × 50 mL). The combined organic matter was dried (MgSO4), concentrated, and the title compound was obtained. 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]quinoline-4-one CDI (153 mg, 0.941 mmol) was added to a solution of 5-fluoro-2-(2-methylpyrazole-3-yl)aniline (90 mg, 0.471 mmol) in NMP (2 mL). The mixture was stirred under microwave irradiation at 150°C for 30 minutes and then cooled to room temperature. The reaction mixture was diluted with water and extracted with DCM. The combined organic matter was dried (MgSO4) and concentrated to obtain the title compound. Tr(METCR1410) = 0.88 min, m / z (ES + ) (M+H) + 218.0, 96%.

[0340] Steps 5-6: Implemented as in Method 3, Steps 3-4. The following was prepared using this route:

[0341] [Table 13] TIFF2026053514000110.tif239152TIFF2026053514000111.tif240151TIFF2026053514000112.t if240152TIFF2026053514000113.tif240152TIFF2026053514000114.tif239151TIFF20260535140 00115.tif241151TIFF2026053514000116.tif240151TIFF2026053514000117.tif240151TIFF202 6053514000118.tif240151TIFF2026053514000119.tif240151TIFF2026053514000120.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]quinoxaline-5-yl)propanamide 3-(7-fluoro-4-oxo-pyrrolo[1,2-a]quinoxaline-5-yl)propanoic acid (prepared according to Method 3, 100 mg, 0.365 mmol) was dissolved in DMF (3 mL), and then 5-(benzyloxy)pyridine-2-amine (110 mg, 0.547 mmol), HATU (208 mg, 0.547 mmol), and DIPEA (0.19 mL, 1.09 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, extracted with RINKAN (3×), dried, and concentrated to dryness using MgSO4. The residue was ground with DCM / MeOH to obtain 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]quinoxaline-5-yl}-N-(5-hydroxypyridine-2-yl)propanamide N-[5-(benzyloxy)pyridine-2-yl]-3-{7-fluoro-4-oxo-4H,5H-pyrrolo[1,2-a]quinoxaline-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 mixture 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 obtain 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 extract was dried and concentrated. Further purification by column chromatography (silica, toluene-heptane mixture) yielded 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-methoxypyridine 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 under vacuum to obtain the title compound. Tr(METCR1410) = 1.10 min, (ES) + [M+H] + = 202.1 / 204.1, 100%.

[0350] Step 3: 7-Fluoro-5-{3-[(5-methoxypyridine-2-yl)oxy]propyl}-4H,5H-pyrrolo[1,2-a]quinoxaline-4-one 7-Fluoro-5H-pyrrolo[1,2-a]quinoxaline-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-methoxypyridine (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 under vacuum and ground with water (5 mL). Further purification by column chromatography (silica, Â-heptane mixture) yielded 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-fluoropyrrolo[1,2-a]quinoxalin-4-one 7-Fluoro-5H-pyrrolo[1,2-a]quinoxaline-4-one (300 mg, 1.48 mmol) was added to a suspension of sodium hydride (60%, 59 mg, 1.48 mmol) in DMF (3.5 mL) stirred 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 mixture was stirred under nitrogen at 80°C for 24 hours. After this, an additional 2-azidoethyl 4-methylbenzenesulfonate (120 mg, 0.48 mmol) was added, and the reaction mixture was stirred at 80°C for another 24 hours. The reaction mixture was diluted with water and ground for 30 minutes. The solid was filtered, dried, and purified by column chromatography (silica, heptane, 0-50% RINKAN) to obtain 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]quinoxaline-5-yl)ethyl]-4-methyl-benzamide Triphenylphosphine (235 mg, 0.896 mmol) was added to a solution of 5-(2-azidoethyl)-7-fluoropyrrolo[1,2-a]quinoxaline-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 product 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 product was concentrated to dryness and purified by preparative HPLC (MeCN-water, 0.1% formic acid) to obtain 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 were also prepared using this route:

[0356] [Table 14]

[0357] Method 13 Scheme of Method 13

[0358] [ka]

[0359] [Example 13-1] Step 1: 2-(3,4-dihydro-1H-isoquinoline-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 at 60°C for 4 hours. 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 obtain 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-isoquinoline-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. A further 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 obtain the title compound. The product was used without further purification.

[0361] Step 3: 7-Fluoro-5-[2-(1,2,3,4-tetrahydroisoquinoline-2-yl)ethyl]-4H,5H-pyrrolo[1,2-a]quinoxaline-4-one 7-Fluoro-5H-pyrrolo[1,2-a]quinoxaline-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 under vacuum and ground with water (5 mL). Further purification by basic preparative HPLC yielded 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 were also prepared using 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. Then, tert-butyl N-(2-aminoethyl)carbamate (2.94 g, 18.0 mmol) was 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 × 25 mL). The aqueous solution was concentrated and purified by column chromatography (silica, siRNA-heptane mixture) to obtain 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]quinoxaline-5-yl)ethyl]carbamate Cs2CO3 (1.49 g, 4.56 mmol) and 1-fluoro-2-nitrobenzene (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 overnight at 60°C. The reaction mixture was concentrated. The residue was divided between water (5 mL) and ethyl acetate (5 mL) and extracted with ethyl acetate (2 × 5 mL). The combined organic matter was dried (MgSO4) and concentrated under vacuum. The residue was purified by column chromatography (silica, ethyl acetate-heptane mixture) to obtain 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]quinoxaline-4-one hydrochloride 100 mg, 0.305 mmol of tert-butyl N-[2-(4-oxopyrrolo[1,2-a]quinoxaline-5-yl)ethyl]carbamate was dissolved in 4 M HCl in 10 mL of dioxane and stirred at room temperature for 2 hours. The reaction mixture was filtered to obtain 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]quinoxaline-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]quinoxaline-4-one hydrochloride (25 mg, 0.095 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The title compound was obtained by purification by basic preparative HPLC. 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 were also prepared using 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]quinoxaline-5-yl)ethyl]isoindoline-1,3-dione 7-Fluoro-5H-pyrrolo[1,2-a]quinoxaline-4-one (500 mg, 2.47 mmol) was suspended in DMF (25 mL). K2CO3 (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 overnight at 60°C, then heated at 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 organic matter was dried (MgSO4), filtered, and concentrated. The title compound was obtained by purification by column chromatography (silica, siRNA-heptane mixture). 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]quinoxaline-4-one 2-[2-(7-fluoro-4-oxo-pyrrolo[1,2-a]quinoxaline-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 siRNA (2 × 30 mL), the combined organic layers were dried (MgSO4) and concentrated under reduced pressure to obtain the title compound. Tr(METCR1410) = 0.78 min, m / z (ES + ) (M+H) + 246.0, 43%.

[0376] Step 3: Implemented as in Method 14, Step 4. The following was prepared using 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]quinoline-4-one 7-Fluoro-1-methyl-5H-pyrazolo[4,3-c]quinoline-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 at 60°C for 24 hours. 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 at 60°C for a further 3 days. The reaction mixture was concentrated under vacuum and partitioned between DCM (50 mL) and water (50 mL). The organic phase was separated, dried (MgSO4), filtered, and concentrated under vacuum. The title compound was obtained by further purification using column chromatography (silica, dimethylheptane mixture). 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]quinoline-5-yl)acetaldehyde 5-(1,3-dioxolan-2-ylmethyl)-7-fluoro-1-methylpyrazolo[4,3-c]quinoline-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 overnight at 60°C. The solvent was removed under vacuum, and the residue was partitioned between DCM and water. The organic phase was dried (MgSO4), filtered, and concentrated to obtain 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]quinoline-4-one A solution of 2-(7-fluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinoline-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), stirred for 1 hour, and then STAB (157 mg, 0.741 mmol) was gradually added, and the mixture was stirred for a further 4 hours. The reaction mixture was concentrated under vacuum, and the residue was partitioned between DCM and water. The organic layer was dried (MgSO4), filtered, and concentrated under vacuum. Further purification using an SCX cartridge yielded 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]quinoline-4-one 5-[2-(benzylamino)ethyl]-7-fluoro-1-methyl-pyrazolo[4,3-c]quinoline-4-one (90 mg, 0.257 mmol) was dissolved in ethanol (9 mL), and palladium-supported carbon (10%, 27 mg, 0.0257 mmol) was added. The mixture was stirred under H2 gas at room temperature for 4 hours. The mixture was filtered, and the filtrate was concentrated under vacuum to obtain the title compound. Tr(METCR1410) = 0.71 min, m / z (ES + ) (M+H) + 260.8, 93%.

[0384] Step 5: Implemented as in Method 14, Step 4. The following was prepared using this route:

[0385] [Table 18]

[0386] Method 17 Scheme of Method 17

[0387] [ka]

[0388] [Example 17-1] Steps 1-2: Method 14, carried out as in Steps 1-2. Steps 3-4: Implemented as in Method 2, Steps 4-5. The following was prepared using this method: (1SR,2SR)-N-(5-methoxypyridine-2-yl)-2-{4-oxo-4H,5H-pyrrolo[1,2-a]quinoxaline-5-yl}cyclobutan-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 degassed with N2 for 5 minutes under sonication. 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 mixture was diluted with  (40 mL) and washed with water (50 mL). The aqueous layer was further extracted with  (2 × 40 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. The crude product was adsorbed onto silica and purified by column chromatography (silica, heptane, 0-20% siRNA) to obtain 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 4M hydrogen chloride in dioxane (0.77 mL, 3.06 mmol) was added to a solution of tert-butyl-[3-(6-methoxy-3-pyridyl)propoxy]-dimethylsilane (224 mg, 0.56 mmol) in THF (5 mL) and stirred at room temperature. The reaction mixture was diluted with saturated aqueous solution NaHCO3 and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. The crude product was purified by column chromatography (10-100% ethyl acetate in silica and heptane) to obtain 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-methoxypyridine 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 heated to room temperature for 6 hours. The reaction mixture was concentrated to obtain the title compound. This 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]quinoxaline-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-methoxypyridine (22 mg, 0.119 mmol) was added. The reaction mixture was stirred overnight at 60°C. The reaction product was partitioned between DCM and water and extracted via a Telos phase separator. The aqueous layer was extracted more than twice, and the combined organic layer was concentrated. The crude product was purified by acidic preparative HPLC to obtain 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: Implemented as in Method 9, Steps 2-6. Step 6: N-(2,4-difluorophenyl)-3-(7-fluoro-4-oxo-1H-pyrazolo[4,3-c]quinoline-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]quinoline-5-yl)-N-(2,4-difluorophenyl)propanamide (137 mg, 0.288 mmol) in formic acid (10 mL). The reaction mixture was stirred in a sealed tube at 60°C for 2 hours. The reaction mixture was cooled to room temperature, diluted with MeOH (130 mL), filtered through Celite, and concentrated under vacuum. The residue was ground with the minimum volume of MeOH to obtain 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]quinoline-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]quinoline-5-yl)propanamide (5.0 mg, 0.013 mmol) and Cs2CO3 (6.3 mg, 0.020 mmol) in anhydrous DMSO (0.5 mL). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated and purified by acidic preparative HPLC to obtain the positional isomers of the title compound. 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 were also prepared using this route:

[0400] [Table 19]

[0401] method 20 Scheme of Method 20

[0402] [ka]

[0403] [Example 20-1] Step 1: Benzyl 2,3,3-triduteriopropane-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) was added dropwise to DMF (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with ₹ (10 mL) and washed with water (3 × 2 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by column chromatography to obtain 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, at 95%.

[0404] Step 2: 2,3,3-Triduterio-3-(7-Fluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinoline-5-yl)propanoic acid 7-Fluoro-1-methyl-5H-pyrazolo[4,3-c]quinoline-4-one (100 mg, 0.460 mmol), 2M sodium hydroxide (0.23 mL, 0.460 mmol), benzyl 2,3,3-triduteriopropa-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 hour. The reaction mixture was diluted with water (3 mL) and extracted with ELISA (10 mL). The organic fraction was concentrated under vacuum. K2CO3 (64 mg, 0.460 mmol), THF (2 mL), and methanol (2 mL) were added to the residue. The reaction mixture was stirred at room temperature for 0.5 hours and concentrated under vacuum. The residue was acidified to pH 3 using 2M HCl, and the resulting precipitate was collected and dried by vacuum filtration to obtain the title compound. The filtrate was extracted with chloroform:IPA (3:1, 3 × 5 mL). Using a separator cartridge, the combined organic matter was dried and concentrated under vacuum together with the original precipitate to obtain 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]quinoline-5-yl}(2,3,3-2H3)propanamide A solution of 2,3,3-triduterio-3-(7-fluoro-1-methyl-4-oxopyrazolo[4,3-c]quinoline-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 under vacuum, and the residue was purified by column chromatography. The product-containing fraction was concentrated under vacuum, and the residue was further purified by grinding with ethanol to obtain 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 Scheme of Method 21

[0407] [ka]

[0408] [Example 21-1] Step 1: 4,5-difluoro-2-(2-methylpyrazole-3-yl)aniline The reaction was carried out as a 2 × 250 mg reaction in separate reaction tubes. The reaction was carried out in parallel and under identical conditions as follows. After the reaction was complete, the products 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 product was heated in a sealed tube at 85°C for 18 hours. The mixture was cooled to room temperature and then concentrated under vacuum on silica. The title compound was obtained by purification by flash column chromatography. 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: Implemented as in Method 9, Step 4. Step 3: 3-(7,8-difluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinoline-5-yl)propanoic acid 7,8-Difluoro-1-methyl-5H-pyrazolo[4,3-c]quinoline-4-one (276 mg, 1.17 mmol), tetrabutylammonium bromide (189 mg, 0.59 mmol), ethyl acrylate (0.25 mL, 2.35 mmol), and K2CO3 (162 mg, 1.17 mmol) were combined in THF (2 mL), and the reaction mixture was heated at 80°C for 4 hours. The reaction mixture was cooled to room temperature, and THF (2 mL) was added, followed by 2 M NaOH (0.59 mL, 1.17 mmol). The reaction mixture was vigorously stirred at room temperature for 18 hours. Volatile substances were removed under vacuum, and the aqueous phase was acidified with 2 M HCl. The resulting precipitate was filtered to obtain 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]quinoline-5-yl}-N-(2,4-difluorophenyl)propanamide 3-(7,8-difluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinoline-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 ethyl acetate) (0.85 mL, 1.74 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. Further addition of 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]quinoline-5-yl)propanoic acid (357 mg, 1.16 mmol) was added, and the reaction mixture was stirred at room temperature for another 3 hours. Water was added, and the solid precipitated, which was then filtered. The precipitate was washed with water, ethyl acetate, and ethyl acetate. The title compound was obtained by purification by basic preparative HPLC. 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 were also prepared using this route:

[0412] [Table 20]

[0413] Method 22 Scheme of Method 22

[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) under N2 conditions at room temperature. Acryloyl chloride (1.9 mL, 23.2 mmol) was added dropwise over 5 minutes. The suspension was stirred overnight at room temperature, filtered, and concentrated to obtain a solid. The solid was ground with heptane and dried under vacuum to obtain 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: Method 21 was carried out as in Step 1. Step 3: Implemented as in Method 9, Step 4. Step 4: N-(2,4-difluorophenyl)-3-{7-fluoro-3-methyl-4-oxo-3H,4H,5H-pyrrolo[2,3-c]quinoline-5-yl}propanamide 7-Fluoro-3-methyl-5H-pyrrolo[2,3-c]quinoline-4-one (50 mg, 0.231 mmol), K2CO3 (45 mg, 0.324 mmol), and N-(2,4-difluorophenyl)propa-2-enamide (0.10 mL, 0.463 mmol) were combined in DMF (1 mL) in a pressure tube, and the reaction mixture was heated at 80°C for 3 hours. 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, sonicated until dissolution was almost complete, then cooled to 4°C for 1.5 hours, and filtered. The collected solid was dried in an oven to obtain 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 Scheme of Method 23

[0418] [ka]

[0419] [Example 23-1] Step 1: 2,4-difluoro-1,3-diiodo-5-nitrobenzene 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. Potassium iodide (681 mg, 4.10 mmol) was then 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 mixture was heated to 50°C and stirred for 2 hours. The reaction mixture was cooled, then poured into ice (50 mL), and extracted with TBME. The combined organic matter was washed with sodium thiosulfate solution (10%), dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by column chromatography to obtain 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-diiodoaniline 2,4-Difluoro-1,3-Diiodo-5-nitrobenzene (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 hour. The crude product mixture was cooled to room temperature, filtered, and washed with ethanol. The filtrate was concentrated under vacuum, and the residue was partitioned between DCM and 1 M aqueous Na2CO3. The organic phase was dried (hydrophobic frit) and concentrated to obtain 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]quinoline-4-one 7-Fluoro-1-methyl-5H-pyrazolo[4,3-c]quinoline-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 a pressure tube in acetonitrile (20 mL) and stirred at 60°C for 2 hours. The cooled reaction mixture was poured into a saturated solution of NaHCO3 (20 mL). The resulting precipitate was filtered, washed with 10% sodium thiosulfate aqueous solution (10 mL) and water (10 mL), and dried overnight under vacuum at 40°C to produce 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: Method 21 was implemented as in Steps 3-4. The following was prepared using this route:

[0423] [Table 21]

[0424] Method 24 Scheme of Method 24

[0425] [ka]

[0426] [Example 24-1] Step 1: Implemented as in Method 9, Step 6. Step 2: 3-{7-fluoro-1-methyl-4-oxo-1H,4H,5H-pyrazolo[4,3-c]quinoline-5-yl}-N-[2-fluoro-4-(tributylstannyl)phenyl]propanamide A suspension of hexabutyldistannan (0.60 mL, 1.18 mmol) and N-(2-fluoro-4-iodophenyl)-3-(7-fluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinoline-5-yl)propanamide (300 mg, 0.590 mmol) in anhydrous toluene (30 mL) was degassed in a pressure tube with N2 for 5 minutes. Pd(PPh3)4 (136 mg, 0.118 mmol) was added, the vial was sealed, and the reaction mixture was stirred at 90°C for 6 hours. The cooled reaction mixture was filtered through Celite (eluted with toluene). The filtrate was separated by brine, and the organic fraction was extracted with toluene. The combined organic matter was dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by column chromatography to obtain 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]quinoline-5-yl)propanamide DMA (3 mL) was added under nitrogen to a vial containing 3-(7-fluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinoline-5-yl)-N-(2-fluoro-4-tributylstannyl-phenyl)propanamide (10 mg, 0.015 mmol), pyridine (0.018 mL, 0.223 mmol), copper(II) trifluate (11 mg, 0.030 mmol), 18-crown-6 (2.0 mg, 7.45 μmol), and potassium fluoride (3.5 mg, 0.060 mmol). The reaction mixture was stirred at 100 °C for 0.5 hours. The reaction mixture was concentrated under vacuum and partitioned between DCM and water. The organic phase was extracted, dried (in a phase separator cartridge), and concentrated under vacuum. The resulting residue was dissolved in acetonitrile and methanol for purification by acidic phase preparative HPLC to obtain 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 Scheme of Method 25

[0429] [ka]

[0430] [Example 25-1] Step 1: 2-Fluoro-4-trimethylstannyl-aniline A suspension of hexamethyldistannan (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 N2 for 5 minutes. Pd(PPh3)4 (731 mg, 0.63 mmol) was added under nitrogen. The reaction mixture 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 on silica under vacuum. The title compound was obtained by purification by flash column chromatography and concentration of the fraction under a nitrogen stream. 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]quinoline-5-yl)-N-(2-fluoro-4-trimethylstannyl-phenyl)propanamide A solution of 3-(7-fluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinoline-5-yl)propanoic acid (300 mg, 1.04 mmol), 2-fluoro-4-trimethylstannylaniline (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 under vacuum, and DCM and water were added. The organic phase was separated, dried (hydrophobic frit), and concentrated under vacuum. The crude residue was purified by flash column chromatography to produce 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]quinoline-5-yl)propanamide DMA (5 mL) was added under nitrogen to a vial containing 3-(7-fluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinoline-5-yl)-N-(2-fluoro-4-trimethylstannyl-phenyl)propanamide (20 mg, 0.032 mmol), pyridine (0.039 mL, 0.484 mmol), copper(II) trifluate (23 mg, 0.065 mmol), 18-crown-6 (4.3 mg, 0.016 mmol), and potassium fluoride (7.5 mg, 0.129 mmol), and the container was stirred at 100°C for 3 hours. The reaction mixture was concentrated under vacuum and partitioned between DCM and water. The organic phase was extracted, washed with water (x3), dried (in a phase separator cartridge), and concentrated under vacuum. 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 obtain 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-methylpyrazole-3-yl)aniline The following mixtures were divided into eight pressure vials: 5-bromo-2-iodoaniline (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 vials were degassed with N2 for 5 minutes, then Pd(PPh3)4 (1.94 g, 1.68 mmol) was added, and the mixture was degassed for another 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 ELISA. The combined organic extract was dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography to obtain 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]quinoline-4-one CDI (4.01 g, 24.8 mmol) was added to a solution of 5-bromo-2-(2-methylpyrazole-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 obtain 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]quinoline-5-yl)propanoic acid A suspension of 7-bromo-1-methyl-5H-pyrazolo[4,3-c]quinoline-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 without solvent at 80°C for 3 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in THF (25 mL), then 2 M NaOH (13 mL, 25.4 mmol) was added, and the reaction mixture was stirred at room temperature for 45 minutes. The reaction mixture was concentrated under vacuum to remove THF, acidified to pH 2-3 using 6 M aqueous HCl, and the resulting aqueous solution was extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4 and concentrated under vacuum. The title compound was obtained by purification by grinding with ethyl acetate. 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]quinoline-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]quinoline-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 hours. The reaction mixture was concentrated under vacuum and partitioned between water and DCM. The organic fraction was separated, and the aqueous phase was re-extracted with further DCM. The combined organic extract was washed with water and brine, dried (hydrophobic frit), and concentrated under vacuum. The crude residue was ground with EtOH to obtain 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]quinoline-5-yl]propanamide A suspension of hexamethyldistannan (355 mg, 1.08 mmol) and 3-(7-bromo-1-methyl-4-oxo-pyrazolo[4,3-c]quinoline-5-yl)-N-(2,4-difluorophenyl)propanamide (250 mg, 0.54 mmol) in anhydrous toluene (25 mL) was sonicated, degassed in a pressure tube under N2 for 5 minutes, and then Pd(PPh3)4 (125 mg, 0.108 mmol) was added 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 further with toluene. The filtrate was partitioned with brine to separate the organic fraction. The combined organic matter was dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by flash column chromatography to obtain 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]quinoline-5-yl)propanamide DMA (4 mL) was added under nitrogen to a vial containing N-(2,4-difluorophenyl)-3-(1-methyl-4-oxo-7-trimethylstannyl-pyrazolo[4,3-c]quinoline-5-yl)propanamide (20 mg, 0.037 mmol), pyridine (0.044 mL, 0.550 mmol), copper(II) trifluate (27 mg, 0.074 mmol), 18-crown-6 (4.8 mg, 0.018 mmol), and potassium fluoride (8.5 mg, 0.147 mmol). The reaction mixture was stirred at 100°C for 1.5 hours. The product was observed by LC-MS tracing by comparing the retention time with that of 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]quinoline-5-yl)propanoylamino]phenyl]boronic acid DIPEA (1.0 mL, 5.70 mmol) was added to a solution of T3P (50% in ethyl acetate, 1.4 mL, 2.85 mmol), 3-(7-fluoro-1-methyl-4-oxo-pyrazolo[4,3-c]quinoline-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 under vacuum and ground with water. The compound was further purified by grinding from acetonitrile (4 mL) to obtain 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]quinoline-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]quinoline-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 diethyl boron trifluoride (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 mixture was warmed to room temperature and stirred for 1.5 hours. The reaction mixture was retreated at 0°C with a solution of iodomesitylene diacetate (145 mg, 0.397 mmol) in DCM (3 mL) and stirred overnight at room temperature. After 22 hours, the reaction mixture was retreated at 0°C with a solution of iodomesitylene diacetate (145 mg, 0.397 mmol) in DCM (3 mL), sonicated, and stirred for a further 24 hours. The reaction mixture was cooled to 0°C, treated with boron trifluoride diethyl ether (0.13 mL, 1.08 mmol), stirred for 10 minutes, and then iodomesitylene diacetate (145 mg, 0.397 mmol) in DCM (3 mL) was added. The reaction mixture was warmed to room temperature and stirred overnight. A saturated solution of NaBF4 (50 mL) was added to the reaction mixture. The mixture was stirred for 10 minutes and then filtered. The precipitate (mixture of starting materials and product) was discarded. The layers were separated from the filtrate, and the aqueous layer was extracted with DCM (2 × 50 mL). The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated. The crude product was ground in DCM (2 × 3 mL) to obtain 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]quinoline-5-yl)propanamide A mixture of copper(II) trifluate (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]quinoline-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 N2 for 5 minutes before reaction) was stirred under N2 in a pressure vial at 85°C for 30 minutes. The reaction was quenched with water (1 mL) and concentrated under vacuum. The residue was purified by acidic preparative HPLC to obtain the title compound. Tr(MET-uHPLC-AB-101) = 2.81 min, m / z (ES + ) (M+H) + 401.1, 93%.

[0446] Method 28 Scheme of Method 28

[0447] [ka]

[0448] [Example 28-1] Step 1: 1,2-Dibenzyloxy-4-bromo-5-nitrobenzene 1,2-Dibenzyloxy-4-bromobenzene (1.00 g, 2.71 mmol) was suspended in acetic acid (15 mL), and the mixture was heated to 50°C until it dissolved. The solution was then cooled to room temperature, and nitric acid (70%, 0.78 mL, 12.2 mmol) was slowly added dropwise. The reaction mixture 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 filtered. The solid was dissolved in DCM and washed with saturated aqueous solution of NaHCO3 until the aqueous phase remained basic. The organic matter was dried (hydrophobic frit), concentrated under vacuum, and the title compound was obtained. 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 were observed, 96%.

[0449] Step 2: Method 21 was carried out as in Step 1. Step 3: 4,5-Dibenzyloxy-2-(2-methylpyrazole-3-yl)aniline Ammonium chloride (722 mg, 13.5 mmol) was added to a suspension of 5-(4,5-dibenzyloxy-2-nitrophenyl)-1-methylpyrazole (676 mg, 1.63 mmol) in a mixture of water (4 mL) and ethanol (6 mL), followed by the gradual addition of iron powder (454 mg, 8.14 mmol). The reaction mixture was then stirred at 70°C for 75 minutes, cooled, filtered through Celite, and washed with ethyl acetate. The filtrate was washed with brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain 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]quinoline-4-one 4,5-Dibenzyloxy-2-(2-methylpyrazole-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 at 120°C for 20 minutes under microwave irradiation. The reaction mixture was carefully poured onto water. The precipitate was collected by filtration and washed with further 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: Method 21 was carried out as in Step 3. Step 6: 3-(7,8-dibenzyloxy-1-methyl-4-oxo-pyrazolo[4,3-c]quinoline-5-yl)-N-(2,4-difluorophenyl)propanamide 3-(7,8-dibenzyloxy-1-methyl-4-oxo-pyrazolo[4,3-c]quinoline-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 under vacuum. Water and a small amount of pharmaceutically acceptable HCl were added, and the resulting precipitate was filtered. The solid was washed with further pharmaceutically acceptable HCl, and the organic phase from the filtrate was separated from the aqueous phase, dried (hydrophobic frit), and concentrated under vacuum to produce 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]quinoline-5-yl}propanamide 3-(7,8-dibenzyloxy-1-methyl-4-oxopyrazolo[4,3-c]quinoline-5-yl)-N-(2,4-difluorophenyl)propanamide (52 mg, 0.0875 mmol) was dissolved in ethanol (6 mL) and ethyl acetate (6 mL) under an N2 atmosphere, and Pd(OH)2 (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 ethyl acetate, ethanol, and DCM. The filtrate was concentrated under vacuum and purified by column chromatography to obtain 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 the radioligand-binding assay (RBA), the MBP-HTT(1-89)Q46-His(6×)("Exon1-Q46") protein was generated 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 hours. The aggregated Exon1-Q46 was pelletized by centrifugation at 13,000 rpm for 5 minutes in a benchtop centrifuge and redissolved in the same volume of assay buffer. The test compound was 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 room temperature for 20 minutes in 100 μL / well (pp, round-bottom) 96-well plates. Then, ligand was added at 50 μL / well and incubated at 37°C for 60 minutes. The final assay concentrations were 1 μM to 30 pM of the test compound, 1 μM of Exon1-Q46 protein (equivalent monomer concentration), and 0.3 nM of ligand. 3 The sample was H3-methyl]-5-((5-methoxypyridine-2-yl)methoxy)-2-(pyrazine-2-yl)benzo[d]oxazole. The sample was transferred to a GF / B filter plate and washed twice with PBS (200 μL) using a Filtermate Harvester. After drying the filter plate at 55°C for 1 hour, the back of the plate was sealed with foil, 30 μL / well of scintillation fluid (Packard MicroScint 40) was added, and the plate was incubated in a dark room for 15 minutes and counted with a MicroBeta reader. For analysis, replicated data from an independent assay plate were used for the vehicle's control well (0% inhibition) and 1 μM unlabeled [ 3 The results were normalized to 0% and 100% inhibition using H3-methyl]-5-((5-methoxypyridine-2-yl)methoxy)-2-(pyrazine-2-yl)benzo[d]oxazole (100% inhibition). IC 50The values ​​use normalized replicated data, and in the overall fit, four variables (top, bottom, slope, IC) are used. 50 This was determined using an S-order inhibition model employing ).

[0454] The results for various example compounds are shown in the table below (+++<100nM;++100~500;+500~10000;ND: Undetermined):

[0455] [Table 22] TIFF2026053514000149.tif239141TIFF2026053514000150.tif83142

[0456] PET imaging examples The following examples illustrate an exemplary and non-restrictive procedure that may be used when conducting PET imaging studies on individuals in a clinical setting. The individual is either untreated or pre-treated with an unlabeled compound. The individual may fast before PET imaging and is permitted to drink water freely. 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 inside a PET camera, and a tracer dose of the imaging agent is administered via an intravenous catheter. Arterial or venous blood samples are taken at appropriate time intervals during the PET scan to analyze and quantify the fraction of unmetabolized compounds in the plasma. Images are obtained for up to 120 minutes. Within 10 minutes of infusion of the radioactive tracer, and at the end of the imaging session, 1 ml blood samples are taken to determine the plasma concentration of any unlabeled imaging agent (or other intervention compounds) that may have been administered prior to the PET tracer.

[0458] A tomographic image is obtained by image reconstruction. For example, a region of interest (ROI) is set on the reconstructed image to determine the distribution of the imaging agent. The region of interest in the brain image 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 a time-radioactivity curve (TAC). The data can be expressed as radioactivity per unit time per unit volume (e.g., μCi / cc / mCi injection dose) or radioactivity per unit volume. TAC data can be processed by various methods known in the art to obtain quantitative parameters, such as binding capacity (BP). For further description of the imaging procedure, 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 those generally understood by those skilled in the art to which this disclosure belongs.

[0460] The disclosures described herein as examples may be appropriately implemented without any one or more elements or limitations not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” and “containing” should be interpreted openly and non-restrictively. Furthermore, the terms and expressions used herein are for illustrative purposes only, not limitation, and there is no intention to exclude equivalents of the illustrated and described features or parts thereof, although various modifications are permitted within the scope of this disclosure.

[0461] All publications, patent applications, patents, and other references mentioned herein are incorporated by explicit reference as well as each is incorporated by explicit reference individually. In case of any conflict, this specification, including definitions, shall prevail.

Claims

1. Formula I: 【Chemistry 1】 [A 1 is C; A 2 is C or N; A 3 CR 21 , NR 3 , or N; A 4 CR 22 , NR 3 , or N; A 5 is CR 23 , NR 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 of these independently consists of hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C. 1～4 Alkyl, C 1～4 Haloalkyl, C 1～4 Alkoxy, C 1～4 Haloalkoxy or C 3～6 It is a cycloalkyl; Each R 3 These are, independently, hydrogen and C 1～4 Alkyl, C 1～4 Haloalkyl, or C 3～6 It is a cycloalkyl; A 6 CR 11 Or N, A 7 CR 12 Or N, A 8 CR 13 Or N, A 9 CR 14 Or N, A 6 , A 7 , A 8 , and A 9 Two or fewer of these are N; R 11 , R 12 , R 13 , and R 14 Each of these is hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, C 1～4 Alkyl, C 1～4 Haloalkyl, C 1～4 Alkoxy, or C 1～4 It is a haloalkoxy; X 1 is C 1～6 Alkyl, C 3～10 Cycloalkyl, C 6～10 It is an aryl, heteroaryl, or heterocyclyl, and X 1 1 to 4 R 4 It is sometimes replaced by; Each R 4 These are independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C. 1～4 Alkyl, C 1～4 Haloalkyl, C 1～4 Alkoxy, or C 1～4 It is a 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 It is an alkoxy; L is -(C(R 6 ) 2 ) m -where m is 1, 2, 3, or 4; Each R 6 These are independently hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C 1～4 Alkyl, C 1～4 Haloalkyl, C 1～4 Alkoxy, or C 1～4 It is a haloalkoxy, or two R 6 It can link with any intervening atom to form a 3- to 6-membered ring; L 1 is C(O), C(O)NR a , NR a C(O), or O, or L 1 It does not exist; R a is hydrogen, C 1～6 Alkyl, or C 1～6 It is a haloalkyl; L 2 These are 1 to 4 R's 7 C is sometimes replaced by 1～2 It is alkylene, or L 2 It does not exist; Each R 7 is independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, C 1～4 alkyl, C 1～4 haloalkyl, C 1～4 alkoxy, or C 1～4 haloalkoxy] Compounds of which are labeled with one or more radioactive isotopes, or isotopic-enriched analogs thereof, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers.

2. Formula I: 【Chemistry 2】 [In the formula, A 1 is C; A 2 is C or N; A 3 CR 21 , NR 3 , or N; A 4 is CR 22 NR 3 or N; A 5 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 of these independently consists of hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C. 1～4 Alkyl, C 1～4 Haloalkyl, C 1～4 Alkoxy, C 1～4 Haloalkoxy or C 3～6 It is a cycloalkyl; Each R 3 These are, independently, hydrogen and C 1～4 Alkyl, C 1～4 Haloalkyl, or C 3～6 It is a cycloalkyl; A 6 CR 11 Or N, A 7 CR 12 Or N, A 8 CR 13 Or N, A 9 CR 14 Or N, A 6 , A 7 , A 8 , and A 9 One of them less than or equal to N is; R 11 , R 12 , R 13 , and R 14 Each of these is hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, C 1～4 Alkyl, C 1～4 Haloalkyl, C 1～4 Alkoxy, or C 1～4 It is a haloalkoxy; X 1 is C 3～10 Cycloalkyl, C 6～10 It is an aryl, heteroaryl, or heterocyclyl, and X 1 1 to 4 R 4 It is sometimes replaced by; Each R 4 These are independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C 1～4 Alkyl, C 1～4 Haloalkyl, C 1～4 Alkoxy, or C 1～4 It is a 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 It is an alkoxy; L is -(C(R 6 ) 2 ) m -where m is 2, 3, or 4; Each R 6 These are independently hydrogen, halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C 1～4 Alkyl, C 1～4 Haloalkyl, C 1～4 Alkoxy, or C 1～4 It is a haloalkoxy; L 1 is C(O), C(O)NR a or NR a C(O) is; R a is hydrogen, C 1～6 Alkyl, or C 1～6 It is a haloalkyl; L 2 These are 1 to 4 R's 7 C is sometimes replaced by 1～2 It is alkylene, or L 2 It does not exist; Each R 7 These are independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, and C. 1～4 Alkyl, C 1～4 Haloalkyl, C 1～4 Alkoxy, or C 1～4 [It is a haloalkoxy] A compound of, However, not 7-bromo-5-(4-oxo-4-(pyrroridine-1-yl)butyl)pyrrolo[1,2-a]quinoxaline-4(5H)-one or N-(2,4-dimethoxyphenyl)-3-(4-oxopyrrolo[1,2-a]quinoxaline-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-dimethylpiperidine-1-yl)-4-oxobutyl]-4H,5H-pyrrolo[1,2-a]quinoxalin-4-one, N-(4-methylphenyl)-3-{4-oxo-4H,5H-pyro Compounds other than lo[1,2-a]quinoxaline-5-yl]propanamide or 7-bromo-5-[4-oxo-4-(piperidine-1-yl)butyl]-4H,5H-pyrrolo[1,2-a]quinoxaline-4-one, or their isotope-enriched analogs, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers.

3. Equation Ia: 【Transformation 3】 The compound according to claim 1 or 2, which is a compound of the same, or an isotope-enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers.

4. Formula IIa: 【Chemistry 4】 [R b ha-L 2 -X 1 And R a This is as defined in claim 1 or 2; or R a and R b It has 1 to 4 R atoms along with any intervening atom. 4 [This may result in the formation of a 3- to 10-membered heterocyclyl ring which is substituted in some cases.] The compound according to claim 1 or 2, which is a compound of the same, or an isotope-enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers.

5. Equation IIb: 【Transformation 5】 [R b ha-L 2 -X 1 And R a This is as defined in claim 1 or 2; or R a and R b It has 1 to 4 R atoms along with any intervening atom. 4 [This may result in the formation of a 3- to 10-membered heterocyclyl ring which is substituted in some cases.] The compound according to claim 1 or 2, which is a compound of the same, or an isotope-enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers.

6. Formula IIc: 【Transformation 6】 [R b ha-L 2 -X 1 And R a This is as defined in claim 1 or 2; or R a and R b It has 1 to 4 R atoms along with any intervening atom. 4 [This may result in the formation of a 3- to 10-membered heterocyclyl ring which is substituted in some cases.] The compound according to claim 1 or 2, which is a compound of the same, or an isotope-enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers.

7. Formula IId: 【Transformation 7】 [R b ha-L 2 -X 1 And R a This is as defined in claim 1 or 2; or R a and R b It has 1 to 4 R atoms along with any intervening atom. 4 [This may result in the formation of a 3- to 10-membered heterocyclyl ring which is substituted in some cases.] The compound according to claim 1 or 2, which is a compound of the same, or an isotope-enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers.

8. R 11 , R 12 , R 13 , or R 14 The compound according to any one of claims 1 to 7, wherein one of the compounds is a halo.

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

10. R 13 The compound according to any one of claims 1 to 8, wherein the compound is a halo.

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

12. R 11 , R 12 , R 13 , or R 14 One of them is C 1～4 A compound according to any one of claims 1 to 7, wherein it is an alkoxy compound.

13. R 11 , R 12 , R 13 , or R 14 The compound according to any one of claims 1 to 8, wherein one of the compounds is methoxy.

14. R 13 The compound according to any one of claims 1 to 7, 12, or 13, wherein is methoxy.

15. R 21 , R 22 , and R 23 The compound according to any one of claims 1 to 14, wherein one of the compounds is methyl.

16. R 21 , R 22 , and R 23 The compound according to any one of claims 1 to 14, wherein one of the compounds is a halo.

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

18. X 1 C 6～10 A compound according to any one of claims 1 to 17, wherein the compound is an aryl compound.

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

20. X 1 The compound according to any one of claims 1 to 17, wherein is a heteroaryl compound.

21. X 1 The compound according to claim 20, wherein is pyridine-2-yl, pyridine-3-yl, or pyridine-4-yl.

22. X 1 The compound according to any one of claims 1 to 17, wherein is a heterocyclyl.

23. X 1 The compound according to claim 22, wherein is 1-piperidinyl, 4-morpholinyl, piperazine-1-yl, piperazine-3-on-1-yl, pyrrolidine-1-yl, or pyridazine-3(2H)-on-6-yl.

24. R 4 is halo, hydroxy, C 1～4 Alkyl, C 1～4 Haloalkyl, or C 1～4 A compound according to any one of claims 1 to 23, wherein it is an alkoxy compound.

25. R 4 The compound according to any one of claims 1 to 24, wherein the compound is a halo.

26. R 4 The compound according to claim 25, wherein is fluoro.

27. X 1 is phenyl, and R 4 The compound according to claim 26, wherein is fluoro.

28. X 1 is phenyl, and R 4 is halo, hydroxy, C 1～4 Alkyl, C 1～4 Haloalkyl, or C 1～4 A compound according to any one of claims 1 to 19, wherein it is an alkoxy compound.

29. X 1 The compound according to claim 28, wherein is 2-fluorophenyl.

30. X 1 The compound according to claim 28, wherein is 2,4-difluorophenyl.

31. X 1 The compound according to claim 28, wherein is 2,5-difluorophenyl.

32. R a and R b However, along with any intervening atom, 1 to 4 R 4 The compound according to any one of claims 3 to 17, which forms a 3 to 10-membered heterocyclyl ring that is optionally substituted by [a certain agent].

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

34. The compound according to any one of claims 1 to 32, wherein m is 3.

35. L 2 A compound according to any one of claims 1 to 34, wherein the compound is not present.

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

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

38. A 6 , A 7 , A 8 , and A 9 One of them is N, and the rest are CR, if applicable. 11 CR 12 CR 13 , or CR 14 The compound according to any one of claims 1 to 36.

39. R 11 , R 12 , R 13 , and R 14 The compound according to any one of claims 1 to 38, wherein each of them is hydrogen.

40. Compounds selected from the compounds in Table 1A, which may be labeled with one or more radioactive isotopes, or isotopic-enriched analogs thereof, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers.

41. A compound according to any one of claims 2 to 40, which is labeled with one or more radioactive isotopes.

42. Compounds selected from the compounds in Table 1B, which are labeled with one or more radioactive isotopes, or isotopic-enriched analogs thereof, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers.

43. 11 C, 13 N, 15 O, and 18 The compound according to claim 1, 41, or 42, comprising one or more positron-emitting radioisotopes selected from F.

44. An imaging agent comprising a compound according to any one of claims 41 to 43, or an isotope-enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers.

45. A method for generating a diagnostic image in an individual, comprising administering an effective amount of the compound described in claim 1 or 41 to 43 or the imaging agent described in claim 44 to the individual, and generating an image of a body part or region of the individual.

46. The method according to claim 45, wherein generating an image of a body part or region of an individual includes detecting the presence or absence of proteins that are prone to aggregation in the image.

47. The method according to claim 46, wherein the protein that readily undergoes aggregation is huntingtin protein (HTT protein).

48. The method according to claim 47, wherein the HTT protein is found in the basal ganglia of the brain.

49. The method according to claim 46 or 47, wherein the presence or absence of protein aggregates corresponds to the presence or absence of neurodegenerative disease.

50. The method according to claim 49, wherein the neurodegenerative disease is selected from Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, prion disease, and spinocerebellar ataxia.

51. The method according to claim 50, wherein the neurodegenerative disease is Huntington's disease (HD).

52. The method according to any one of claims 45 to 51, wherein the effective amount of the imaging agent comprises about 0.1 to about 20 mCi.

53. The method according to claim 52, wherein the effective amount of imaging agent comprises about 10 mCi.

54. The method according to any one of claims 45 to 53, wherein generating an image includes 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.

55. The method according to claim 54, wherein generating an image includes PET imaging.

56. The method according to claim 47 or 48, wherein the HTT protein exists as an oligomer, an aggregate, or a combination thereof.

57. The method according to claim 47 or 48, wherein the HTT protein is a variant.

58. The method according to any one of claims 45 to 57, wherein the body part or body region is the head, spine, limb, chest, or abdomen.

59. The method according to any one of claims 45 to 57, wherein the body part or region of the body is the brain.

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