Heterocyclic Compounds as Monoacylglycerol Lipase (MAGL) Inhibitors.

pubs.acs.org/acsmedchemlett Patent Highlight Heterocyclic Compounds as Monoacylglycerol Lipase (MAGL) Inhibitors Ram W. Sabnis* Cite This: ACS Med. Chem. Lett. 2021, 12, 536−537 ACCESS Read Online Metrics & More Article Recommendations Important Compound Classes. precursor (OPCs) to excitotoxic insults and therefore may be neuroprotective. Additionally, pharmacological inhibition of MAGL increases the number of myelinating OLs in the brain of mice, suggesting that MAGL inhibition may promote differentiation of OPCs in the myelinating OLs in vivo. MAGL as an important decomposing enzyme for both lipid metabolism and the endocannabinoids system, additionally as a part of a gene expression signature, contributes to different aspects of tumorigenesis. The present application describes a series of novel heterocyclic compounds as monoacylglycerol lipase (MAGL) inhibitors for the treatment of neuroinflammation, neurodegenerative diseases, pain, cancer, mental disorders, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, traumatic brain injury, stroke, epilepsy, anxiety, migraine, and depression. Further, the application discloses compounds and their preparation, use, pharmaceutical composition, and treatment. Definitions. X = CR3; m = 0 or 1; n = 0, 1 and 2; and L = −(CH2)p−, −O−, −OCH2−, −CH2OCH2−, −CF2CH2−, −CH2CH2−, −(CR16R17)q−, CH2O−, and −CH2CF2−; or X = N; m = 1; n = 1 or 2; and L = −(CH2)p−, or −CF2CH2−; p = 1, 2, and 3; q = 0 or 1; A = C6−C14-aryl substituted with R4, R5 and R6; 5- to 14-membered heteroaryl substituted with R7, R8 and R9; and 3- to 14-membered heterocycloalkyl substituted with R10, R11 and R12; R1 = H or C1−6-alkyl; R2 = H or C1−6-alkyl and hydroxy-C1−6-alkyl; R3 = H, halogen, OH, C1−6-alkoxy, C1−6-alkyl and halo-C1−6alkyl; R4, R5, R6, R7, R8, R9, R10, R11 and R12 = H, halogen, CN, OH, C1−6-alkyl, halo-C1−6-alkyl, hydroxy-C1−6-alkyl, C1−6-alkanoyl, halo-C1−6-alkyl−CH(OH)-, C1−6-alkoxy, halo-C1−6-alkoxy, SF5, CH3SO2, C3−10-cycloalkyl, C3−10-cycloalkyl substituted with R13, 3- to 14-membered heterocycloalkyl, 3- to 14-membered Title. New Heterocyclic Compounds as Monoacylglycerol Lipase Inhibitors Patent Publication Number. WO 2020/035424 A1 Publication Date. February 20, 2020 Priority Application. EP 18188681.3 Priority Date. August 13, 2018 Inventors. Bell, C.; Benz, J.; Gobbi, L.; Grether, U.; Groebke Zbinden, K.; Hornsperger, B.; Kocer, B.; Kroll, C.; Kuhn, B.; Lutz, M. D. R.; O’Hara, F.; Richter, H.; Ritter, M.; Rombach, D.; Kuratli, M. Assignee Company. F. Hoffmann-La Roche AG, Switzerland, and Hoffmann-La Roche Inc., USA Disease Area. Neuroinflammation, neurodegenerative diseases, pain, cancer, mental disorders, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, traumatic brin injury, stroke, epilepsy, anxiety, migraine, and depression Biological Target. Monoacylglycerol lipase (MAGL) Summary. Endocannabinoids (ECs) are signaling lipids that exert their biological actions by interacting with cannabinoid receptors (CBRs), CB1 and CB2. They modulate multiple physiological processes including neuroinflammation, neurodegeneration, and tissue regeneration. In the brain, the main endocannabinoid, 2-arachidonoylglycerol (2-AG), is produced by diacylglycerol lipase (DAGL) and hydrolyzed by the monoacylglycerol lipase (MAGL). MAGL hydrolyzes 85% of 2-AG, with the remaining 15% being hydrolyzed by ABHD6 and ABDH12. MAGL is expressed throughout the brain and in most brain cell types, including neurons, astrocytes, oligodendrocytes, and microglia cells. Phospholipase A2 (PLA2) enzymes have been viewed as the principal source of AA, but cPLA2-deficient mice have unaltered AA levels in their brain, reinforcing the key role of MAGL in the brain for AA production and regulation of the brain inflammatory process. In addition, genetic and/or pharmacological disruption of MAGL was shown to be protective in several animal models of neurodegeneration and multiple sclerosis. Both cannabinoids and pharmacological inhibition of MAGL attenuate the vulnerability of oligodendrocytes (OLs) and their Published 2021 by American Chemical Society Received: March 13, 2021 Published: March 31, 2021 536 https://doi.org/10.1021/acsmedchemlett.1c00149 ACS Med. Chem. Lett. 2021, 12, 536−537 ACS Medicinal Chemistry Letters pubs.acs.org/acsmedchemlett heterocycloalkyl substituted with R14, and R15, 5- to 14membered heteroaryl, C6−C14-aryl, C6−C14-aryloxy, halo-C6− C14-aryl, and halo-C6−C14-aryloxy; R13, R14 and R15 = C1−6-alkyl, C1−6-alkoxy, halo-C1−6-alkyl, halo-C1−6-alkoxy, halogen, and OH; and R16 and R17 taken together with the carbon atom to which they are attached, form a C3−7-cycloalkyl. Key Structures. ■ Patent Highlight 1. Gilgenkrantz, H.; Mallat, A.; Moreau, R.; Lotersztajn, S. J. Hepatol. 2021, in press. 2. Fowler, C. J. J. Int. Med. 2021, in press. 3. Maramai, S.; Brindisi, M. ChemMedChem 2020, 15, 1985. 4. Grimsey, N. L.; Savinainen, J. R.; Attili, B.; Ahamed, M. Drug Discovery Today 2020, 25, 330. 5. Liu, T.; Liu, X.; Chen, Q.; Shi, Y. Biomed. Pharmacother. 2020, 128, 110314. 6. Deng, H.; Li, W. Acta Pharm. Sin. B 2020, 10, 582. AUTHOR INFORMATION Corresponding Author Ram W. Sabnis − Smith, Gambrell & Russell LLP, Atlanta, Georgia 30309, United States; orcid.org/0000-00017289-0581; Email: Complete contact information is available at: https://pubs.acs.org/10.1021/acsmedchemlett.1c00149 Notes The author declares no competing financial interest. Biological Assay. The MAGL enzymatic assay was performed in a mammal. The compounds described in this application were tested for their ability to inhibit MAGL. The MAGL IC50 (μM) values are shown in the following table. Biological Data. The table below shows representative compounds were tested for MAGL inhibition. The biological data obtained from testing representative examples are listed in the following table. Claims. Total claims: 56 Compound claims: 47 Pharmaceutical composition claims: 1 Use of compound claims: 4 Method of manufacturing claims: 1 Method of treatment claims: 2 Invention claim: 1 Recent Review Articles. 537 https://doi.org/10.1021/acsmedchemlett.1c00149 ACS Med. Chem. Lett. 2021, 12, 536−537  (...truncated)