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CN-122029147-A - Probes for MAGL

CN122029147ACN 122029147 ACN122029147 ACN 122029147ACN-122029147-A

Abstract

The invention provides compounds having the general formula (I) wherein R 1 、R 2 , X, and Y are as described herein, compositions comprising the compounds, methods of making the compounds, and methods of using the compounds.

Inventors

  • J. M. Benz
  • NAZARE MARC
  • F. S. O'Hara
  • J.P. Paul
  • B. PUELLMANN
  • M. RITTER
  • M. Jilu
  • U. M. Glazer
  • M. L. Guberman
  • HE YINGFANG
  • MU LINJING
  • A. R. Hench
  • B. W. Kuhn
  • R.E. MARTIN

Assignees

  • 豪夫迈·罗氏有限公司
  • 苏黎世联邦理工学院

Dates

Publication Date
20260512
Application Date
20241015
Priority Date
20231016

Claims (20)

  1. 1. A compound of formula (I) (I) Or a pharmaceutically acceptable salt thereof, wherein: X is CH and Y is CH 2 , or X and Y together form the group ch=c; r 1 is selected from: ; R 1a is selected from halo-C 1 -C 6 -alkyl and hydroxy-C 1 -C 6 -alkyl, and R 2 is selected from: 、 And ; R 3a and R 3b are each independently selected from hydrogen, C 1 -C 6 -alkyl and 5-to 6-membered heteroaryl; r 3c is selected from F and 18 F; the reporting unit is selected from: ; And (C) sum ; L is selected from –(CH 2 ) p –、–(CH 2 ) 2 -NHC(O)-CH 2 –、–CH 2 -NHC(O)-(CH 2 ) 2 –、–((CH 2 ) 2 O) q -(CH 2 ) 2 – and- (CH 2 ) 2 -(O(CH 2 ) 2 ) q -; n and m are each independently 1 or 2; p is selected from 1, 2, 3, 4 and 5; q is selected from 1,2 and 3, and R is selected from 1,2, 3 and 4.
  2. 2. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is CH and Y is CH 2 .
  3. 3. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R 1 is Wherein R 1a is as defined in claim 1.
  4. 4. A compound of formula (I) according to claim 3, or a pharmaceutically acceptable salt thereof, wherein R 1a is halo-C 1 -C 6 -alkyl.
  5. 5. A compound of formula (I) according to claim 3, or a pharmaceutically acceptable salt thereof, wherein R 1a is selected from CF 3 and hydroxymethyl.
  6. 6. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 3 wherein R 1a is CF 3 .
  7. 7. A compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from: 、 、 、 And ; Wherein R 3a 、R 3b 、R 3c , m, n and R are as defined in claim 1.
  8. 8. A compound of formula (I) according to claim 7, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from: 、 And And wherein: R 3a is selected from hydrogen and C 1 -C 6 -alkyl; R 3b is selected from hydrogen, C 1 -C 6 -alkyl, and 5-to 6-membered heteroaryl; r 3c is selected from F and 18 F; m is 1 or 2, and N is 1.
  9. 9. A compound of formula (I) according to claim 8, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from: 、 And And wherein: r 3a is selected from hydrogen and methyl; r 3b is selected from hydrogen, methyl and pyrrolyl; r 3c is selected from F and 18 F; m is 1 or 2, and N is 1.
  10. 10. A compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from: 、 、 、 、 、 And And wherein: r 3c is selected from F and 18 F.
  11. 11. A compound of formula (I) according to claim 10, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from: 、 、 、 And And wherein: r 3c is selected from F and 18 F.
  12. 12. A compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 3c is F.
  13. 13. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: X is CH and Y is CH 2 ; x and Y together form the group ch=c; r 1 is ; R 1a is selected from halo-C 1 -C 6 -alkyl and hydroxy-C 1 -C 6 -alkyl; R 2 is selected from: 、 And And wherein: R 3a is selected from hydrogen and C 1 -C 6 -alkyl; R 3b is selected from hydrogen, C 1 -C 6 -alkyl, and 5-to 6-membered heteroaryl; r 3c is selected from F and 18 F; m is 1 or 2, and N is 1.
  14. 14. A compound of formula (I) according to claim 13, or a pharmaceutically acceptable salt thereof, wherein: X is CH and Y is CH 2 ; r 1 is ; R 1a is selected from halo-C 1 -C 6 -alkyl and hydroxy-C 1 -C 6 -alkyl; R 2 is selected from: 、 、 、 、 、 And And wherein: r 3c is selected from F and 18 F.
  15. 15. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 14, wherein: X is CH and Y is CH 2 ; r 1 is ; R 1a is selected from CF 3 and hydroxymethyl; R 2 is selected from: 、 、 、 、 、 And And wherein: R 3c is F.
  16. 16. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from: 1, 3-hexafluoropropan-2-yl 6- ((5, 5-difluoro-5H-4λ4,5λ4-dipyrrolo [1,2-c:2',1' -f ] [1,3,2] diazaboro-cyclohexatrien-10-yl) methyl) -2-azaspiro [3.3] heptane-2-carboxylate; 6- ((5, 5-difluoro-3- (1H-pyrrol-2-yl) -5H-4l4,5l 4-dipyrrolo [1,2-c:2',1' -F ] [1,3,2] diazaboro-trien-10-yl) methyl) -2-azaspiro [3.3] heptane-2-carboxylic acid [ 18 F ] -1, 3-hexafluoropropan-2-ester; 1, 3-hexafluoropropan-2-yl 6- ((5, 5-difluoro-3- (1H-pyrrol-2-yl) -5H-4l4,5l 4-dipyrrolo [1,2-c:2',1' -f ] [1,3,2] diazaboro-trien-10-yl) methyl) -2-azaspiro [3.3] heptane-2-carboxylate; 1, 3-hexafluoropropan-2-ester of 6- ((5, 5-difluoro-3-methyl-5H-4 l4,5l 4-dipyrrolo [1,2-c:2',1' -f ] [1,3,2] diazaboro-10-yl) methyl) -2-azaspiro [3.3] heptane-2-carboxylic acid; 1, 3-hexafluoropropan-2-ester of 6- ((5, 5-difluoro-3, 7-dimethyl-5H-4 l4,5l 4-dipyrrolo [1,2-c:2',1' -f ] [1,3,2] diazaboro-trien-10-yl) methyl) -2-azaspiro [3.3] heptane-2-carboxylic acid; 6- ((5, 5-difluoro-5H-4 l4,5l 4-dipyrrolo [1,2-c:2',1' -f ] [1,3,2] diazaborocyclohexatrien-10-yl) methyl) -2-azaspiro [3.3] heptane-2-carboxylic acid (R) -1, 1-trifluoro-3-hydroxypropane-2-ester; 6- ((5, 5-difluoro-3- (1H-pyrrol-2-yl) -5H-4l4,5l 4-dipyrrolo [1,2-c:2',1' -f ] [1,3,2] diazaboro-trien-10-yl) methyl) -2-azaspiro [3.3] heptane-2-carboxylic acid (R) -1, 1-trifluoro-3-hydroxypropane-2-ester; 1, 3-hexafluoropropane-2-ester of 6- (2- (2- (3- (5, 5-difluoro-7, 9-dimethyl-5H-5 l4,6l 4-dipyrrolo [1,2-c:2',1' -f ] [1,3,2] diazaboro-trien-3-yl) propanamido) ethoxy) benzyl) -2-azaspiro [3.3] heptane-2-carboxylic acid; 6- (2- (2- (4- ((4- (dimethylamino) phenyl) but-1, 3-diyn-1-yl) benzamido) ethoxy) benzyl) -2-azaspiro [3.3] heptane-2-carboxylic acid 1, 3-hexafluoropropane-2-ester, and N- (10- (2-carboxy-5- ((5- (2- ((2- (((1, 3-hexafluoropropan-2-yl) oxy) carbonyl) -2-azaspiro [3.3] heptan-6-yl) methyl) phenoxy) pentyl) carbamoyl) phenyl) -7- (dimethylamino) -5, 5-dimethyldibenzo [ b, e ] cyclohexanetrien-3 (5H) -ylidene) -N-methyl-ammonium.
  17. 17. A compound of formula (I) according to any one of claims 1 to 16 for use in monoacylglycerol lipase (MAGL) occupancy studies.
  18. 18. A compound of formula (I) according to any one of claims 1 to 16 for use in diagnostic imaging of monoacylglycerol lipase (MAGL) in mammals.
  19. 19. A compound of formula (I) according to any one of claims 1 to 16 for use in generating monoacylglycerol lipase (MAGL) balance and kinetic binding data.
  20. 20. Use of a compound of formula (I) according to any one of claims 1 to 16 in monoacylglycerol lipase (MAGL) occupancy studies.

Description

Probes for MAGL Technical Field The present invention relates to organic compounds useful as fluorescent, raman or PET probes for monoacylglycerol lipase (MAGL). Background Fluorescent imaging probes have become high resolution tools for research localization (e.g., expression levels and protein distribution in healthy and disease states, structure, kinetics, and function of proteins in living cells) (l.a. Stoddart, l.e. Kilpatrick, s.j. Briddon, s.j. Hill, neuropharmacology 2015, 98, 48-57). Such probes may be applied, for example, to flow cytometry Fluorescence Activated Cell Sorting (FACS) experiments or cell trafficking studies using confocal living cell imaging. Furthermore, fluorescent imaging probes allow for real-time monitoring of ligand-receptor interactions and protein visualization （A. J. Vernall, S. J. Hill, B. Kellam, Br. J. Pharmacol. 2014, 171, 1073–1084; C. Iliopoulos-Tsoutsouvas, R. N. Kulkarni, A. Makriyannis, S. P. Nikas, Expert Opin. Drug Discov.2018, 13, 933–947). with high spatial-temporal accuracy, in addition, such probes offer the potential to generate equilibrium and kinetic binding data in a high-throughput manner without the need to treat radioactive materials using, for example, time-resolved fluorescence resonance energy transfer (TR-FRET). The fluorescent imaging probes may also be used to support the conversion of preclinical pharmacologic animal data to clinical pharmacologic animal data and may be applied to dose selection in humans. They can be used as markers for target engagement, for example, via the generation of ex vivo quantitative receptor binding data in whole blood. Depending on the respective application, the fluorescent imaging probes need to match specific criteria, including affinity, selectivity and specificity for the respective target, favorable photophysical properties, and suitability in different technologies and cell types. Similarly, raman spectroscopic probes are capable of monitoring cell and tissue changes in real time, helping to study drug-target engagement （K. Antonio, Z. Schultz Anal. Chem., 2014, 86(1) 30-46; C. Krafft, J. Popp Anal. Bioanal. Chem., 2015, 407(3) 699-717; Lawson et al, j. Raman spectroscopy, 1997, 28 (2-3), 111-117. In contrast to fluorescent probes, there is a correlation only in the specific raman absorption of the probe, not in the fluorescent properties. The absorption range for reliable raman spectroscopic analysis of biological samples is typically between 1800 cm - and 2800 cm - 1, where raman signals are easily detected and distinguished. [ 18 F ] Positron Emission Tomography (PET) probes labeled with the radioisotope fluorine-18 have significant advantages over fluorescent probes in biomedical imaging (S. Chua, A. Groves, biomedical Imaging: applications AND ADVANCES, 2014). First, the [ 18 F ] -PET probe allows for accurate localization of molecular targets within an organism due to its deep tissue penetration and high spatial resolution. Second, their radioactive nature enables accurate assessment of physiological processes and molecular interactions in vivo by quantitative measurements. The advantages of the fluorescent probe and the [ 18 F ] -PET probe can be achieved by a bimodal [ 18 F ] -BODIPY probe combination (Y. Kwon et al, nucl. Med. Biol. 2021, 93, 22-36). Disclosure of Invention In a first aspect, the present invention provides a compound of formula (I) (I) Or a pharmaceutically acceptable salt thereof, wherein R 1、R2, X and Y are as defined herein. In further aspects, the invention provides compositions comprising, methods of making, and methods of using compounds of formula (I). Drawings Figure 1 shows an HPLC chromatogram of the 18 F-labeled compound described in example 2. Detailed Description Definition of the definition Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed. The term "alkyl" refers to a monovalent or multivalent (e.g., monovalent or divalent) straight or branched chain saturated hydrocarbon radical ("C 1-C6 -alkyl") having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4,5, or 6 carbon atoms). In other embodimen