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JP-7855011-B2 - Isoindlinone compounds and imaging agents for imaging huntingtin protein

JP7855011B2JP 7855011 B2JP7855011 B2JP 7855011B2JP-7855011-B2

Inventors

  • リウ，ロンビン
  • ドミンゲス，セリア
  • バード，ジョナサン
  • ブラウン，クリストファー ジョン
  • チェン，シューメイ
  • クラーク－フルー，ダニエル
  • ミルズ，マシュー ロバート
  • ジョンソン，ピーター デイヴィッド
  • ガダロ，エリス

Assignees

  • シーエイチディーアイ ファウンデーション，インコーポレーテッド

Dates

Publication Date
20260507
Application Date
20220407
Priority Date
20210408

Claims (20)

  1. Formula I: [In the formula, teeth, or and; If present, R1 is hydrogen, C1-6 alkyl, or C1-6 haloalkyl; If present, R 10 is hydrogen, C1-6 alkyl, or C1-6 haloalkyl; Ring A is pyridinyl ; X is either CR 11 or N; R 11 is hydrogen, cyano, hydroxy, halo, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy; Y 1 is either CR 12 or N; Y 2 is either CR 13 or N; R12 and R13 are each hydrogen, hydroxyl, halo, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy; R2 is hydrogen, hydroxyl, halo, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy; L is a C1 - C3 alkylene that is optionally substituted with 1-6 fluorocarbons; R 3 is hydrogen, fluoro, C1-6 alkyl, or C1-6 haloalkyl; Each R4 is independently cyano, hydroxy, halo, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy; Each R 5 is independently cyano, hydroxy, halo, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy; R 6 is hydrogen, cyano, hydroxy, halo, C1-6 alkyl, -SO2F , or L1 - R7 ; L1 is -O-, -SO2- , or -OSO2- ; R7 is hydrogen, C1-6 alkyl, or C1-6 haloalkyl, where the C1-6 alkyl or C1-6 haloalkyl of R7 is optionally substituted with -SO2-aryl, -OSO2 - aryl , 1-6 deuterium atoms, or a combination thereof , and the -SO2 -aryl or -OSO2-aryl is further optionally substituted with cyano, hydroxy, halo, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy; m is 0, 1, 2, or 3; n is 0, 1, or 2. Compounds thereof, or isotope-enriched analogs thereof, pharmaceutically acceptable salts , tautomers, stereoisomers, or mixtures of stereoisomers.
  2. Formula II: The compound according to claim 1, or an isotope-enriched analog thereof, a pharmaceutically acceptable salt , a tautomer, a stereoisomer, or a mixture of stereoisomers.
  3. Formula III: The compound according to claim 1, or an isotope-enriched analog thereof, a pharmaceutically acceptable salt , a tautomer, a stereoisomer, or a mixture of stereoisomers.
  4. Formula IV: The compound according to claim 1, or an isotope-enriched analog thereof, a pharmaceutically acceptable salt , a tautomer, a stereoisomer, or a mixture of stereoisomers.
  5. Formula V: The compound according to claim 1, or an isotope-enriched analog thereof, a pharmaceutically acceptable salt , a tautomer, a stereoisomer, or a mixture of stereoisomers.
  6. Equation VI: The compound according to claim 1, or an isotope-enriched analog thereof, a pharmaceutically acceptable salt , a tautomer, a stereoisomer, or a mixture of stereoisomers.
  7. Formula VII: The compound according to claim 1, or an isotope-enriched analog thereof, a pharmaceutically acceptable salt , a tautomer, a stereoisomer, or a mixture of stereoisomers.
  8. Formula VIII: The compound according to claim 1, or an isotope-enriched analog thereof, a pharmaceutically acceptable salt , a tautomer, a stereoisomer, or a mixture of stereoisomers.
  9. Formula IX: The compound according to claim 1, or an isotope-enriched analog thereof, a pharmaceutically acceptable salt , a tautomer, a stereoisomer, or a mixture of stereoisomers.
  10. Formula X: The compound according to claim 1, or an isotope-enriched analog thereof, a pharmaceutically acceptable salt , a tautomer, a stereoisomer, or a mixture of stereoisomers.
  11. Formula XI: The compound according to claim 1, or an isotope-enriched analog thereof, a pharmaceutically acceptable salt , a tautomer, a stereoisomer, or a mixture of stereoisomers.
  12. Formula XII: The compound according to claim 1, or an isotope-enriched analog thereof, a pharmaceutically acceptable salt , a tautomer, a stereoisomer, or a mixture of stereoisomers.
  13. Formula XIII: The compound according to claim 1, or an isotope-enriched analog thereof, a pharmaceutically acceptable salt , a tautomer, a stereoisomer, or a mixture of stereoisomers.
  14. Formula XIV: The compound according to claim 1, or an isotope-enriched analog thereof, a pharmaceutically acceptable salt , a tautomer, a stereoisomer, or a mixture of stereoisomers.
  15. Formula XV: The compound according to claim 1, or an isotope-enriched analog thereof, a pharmaceutically acceptable salt , a tautomer, a stereoisomer, or a mixture of stereoisomers.
  16. The compound according to claim 1, wherein R1 is hydrogen or C1-6 alkyl.
  17. The compound according to claim 1, wherein R1 is C1-6 alkyl.
  18. The compound according to claim 1, wherein R1 is methyl.
  19. The compound according to claim 1, wherein R2 is hydrogen.
  20. The compound according to claim 1, wherein R3 is hydrogen.

Description

Cross-reference of related patent applications: This application claims priority to U.S. Provisional Patent Application No. 63/172,617, filed 8 April 2021, which is incorporated herein by reference for all purposes. Compounds and imaging agents useful for detecting, treating, or preventing diseases or conditions related to protein aggregation, compositions thereof, and methods of using them are provided herein. 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 have broad diagnostic utility, and their use in evaluating treatment responses and supporting drug development is rapidly expanding. The introduction of high-resolution molecular imaging techniques is seen by many experts as a major breakthrough. PET involves administering a positron-emitting radionuclide tracer to a target and subsequently detecting positron emission (annihilation) events within the body. A radionuclide tracer typically consists of a target molecule containing one or more types of positron-emitting radionuclides. 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 and processes associated with a range of diseases. 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 trinucleotide 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 prevalence of 5 to 10 cases per 100,000 people worldwide, making it the most common hereditary and monogenic neurodegenerative disorder. As with any other medical condition, treatment for hemodialysis (HD) should ideally be initiated at or before the onset of early disease symptoms. Therefore, early indicators of disease onset and reliable pharmacodynamic biomarkers for disease progression are highly desirable. Figure 1 shows the specific and saturated binding of the test radioligand compound over a range of concentrations determined in the cortical tissue of 12-month-old HOM zQ175, an HD mouse model.Figure 2 shows the specific binding of [ 3H ]-compounds 1-6 to various postmortem human brain tissue samples (healthy subjects [CTRL], Huntington's disease [HD], and Alzheimer's disease [AD]).Figure 3 compares the specific binding of [3H]-compounds 1-6 to [ 3H ]-comparative compound 3 and [ 3H ]-comparative compound 4 in various postmortem human brain tissue samples (healthy subjects [CTRL], Huntington's disease [HD], and Alzheimer's disease [ AD ]). The following description provides exemplary embodiments of the Technology. However, it should be recognized that such descriptions are not intended to limit the scope of this disclosure, but rather are provided as exemplary embodiments. Definitions: As used herein, 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. The compounds described herein refer to any compound of any formula described herein, including those of formula I, II, III, IV, V, VI, VII, VII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, 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 in Table 1, or labeled isomers of such compounds as defined herein, or imaging agents or pharmaceutical compositions containing such compounds or labeled compounds. 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. A wavy line drawn through a bond in a structure indicates a specific bond point. Unless chemically or structurally required, no orientation or stereochemistry is indicated or implied by the order in which chemical groups are written or named. The prefix " Cu~v " indicates that, with the exception of further substitutions, the following groups have u to v carbon atoms. For example, " C1~ 6alkyl