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WO2025010392A2 - Inhibiteurs de monoacylglycérol lipase et leur utilisation pour le traitement de troubles neurologiques - Google Patents

Inhibiteurs de monoacylglycérol lipase et leur utilisation pour le traitement de troubles neurologiques Download PDF

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Publication number
WO2025010392A2
WO2025010392A2 PCT/US2024/036852 US2024036852W WO2025010392A2 WO 2025010392 A2 WO2025010392 A2 WO 2025010392A2 US 2024036852 W US2024036852 W US 2024036852W WO 2025010392 A2 WO2025010392 A2 WO 2025010392A2
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compound
formula
methyl
fluoro
optionally substituted
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WO2025010392A3 (fr
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Jacob Matthew Hooker
Alan John Cross
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Psy Therapeutics Inc
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Psy Therapeutics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings

Definitions

  • Epilepsy is a neurological disorder characterized by the occurrence of recurrent and unprovoked seizures. Epilepsy affects about 50 million people worldwide and carries serious neurobiological, cognitive, psychological, and social consequences. Despite the availability of various antiepileptic drugs (AEDs) with different mechanisms of action, over one third of patients are resistant to AEDs, and many suffer adverse effects from medication. Despite the availability of various antiepileptic drugs, a significant proportion of patients continue to experience seizures or encounter adverse effects from medication. Therefore, the development of novel therapeutic approaches is crucial. [0004] One potential strategy that has shown promise is the inhibition of Monoacylglycerol Lipase (MAGL), an enzyme involved in the metabolism of endocannabinoids.
  • MAGL Monoacylglycerol Lipase
  • MAGL inhibition offers a unique mechanism of action that may provide effective seizure control and minimize adverse effects.
  • MAGL is the principal enzyme responsible for the in vivo degradation of 2- arachidonoyl glycerol (2-AG), an endogenous ligand of the cannabinoid receptors (e.g., CB1 and CB2).
  • MAGL inhibition increases accumulation of the CB1/2 receptor agonist 2-arachidonoyl glycerol (2-AG), and reduces arachidonic acid (AA) and prostaglandin levels in the brain and peripheral tissues.
  • Irreversible MAGL inhibitor compounds such as JZL-184, increase brain and peripheral 2-AG and reduce brain AA, however tolerance can develop with chronic irreversible MAGL inhibition.
  • a reversible MAGL inhibitor is used to increase 2-AG within the central nervous system.
  • the invention is based in part on the discovery that a reversible MAGL inhibitor can transiently increase 2-AG in the brain of certain animal models.
  • methods of transiently increasing 2-AG in the brain comprise the administration of a reversible MAGL inhibitor compound where the pharmacodynamic half-life (e.g., as measured by the transient increase in 2-AG in the brain) is within less than twice the pharmacokinetic half-life of the compound (e.g., as measured by the half-life of the compound in the plasma).
  • a method of treatment comprises oral administration of a reversible MAGL inhibitor to a subject in a therapeutically effective amount resulting in the transient increase of 2-AG in the brain of the subject that is characterized by a ratio of less than 2 between the half-life of transient 2-AG increase in the brain and the plasma half-life of the compound in the blood plasma.
  • a covalent small molecule MAGL inhibitor such as JZL 184
  • the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) is a lipid-signaling molecule in the central nervous system (CNS) that acts as an agonist of the CB1 receptor and the primary endogenous ligand for the CB2 receptor.
  • CB1 is the primary target of ⁇ 9- tetrahydrocannabinol.
  • 2-AG levels have been shown to increase in the amygdala in response to repeated stress exposure, suggesting a physiologic role for this system in guarding against the development of stress-induced pathology.
  • a method of treating a MAGL-mediated disease in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound disclosed herein, such as a compound selected from the group consisting of: (2,4-difluoro-5-hydroxyphenyl) ⁇ 6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2- spiro[3.3]heptyl ⁇ methanone (Compound 126); 4-hydroxy-2-( ⁇ 6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2- spiro[3.3]heptyl ⁇ carbonyl)benzonitrile (Compound 128); [4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl] ⁇ 6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2- spiro[3.3]heptyl ⁇ methanone
  • the disclosure provides a method for treating a monoglycerol lipase mediated disease or disorder.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound herein.
  • MAGL inhibition represents a promising therapeutic approach for epilepsy by modulating the endocannabinoid system.
  • endocannabinoids particularly 2-arachidonoylglycerol
  • MAGL inhibitors can potentially restore the balance between excitatory and inhibitory signaling, reduce neuronal hyperexcitability, and exert neuroprotective effects.
  • the method comprises administering to the subject a therapeutically effective amount of a compound selected from the group consisting of (2,4-difluoro-5-hydroxyphenyl) ⁇ 6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2- spiro[3.3]heptyl ⁇ methanone (Compound 126); 4-hydroxy-2-( ⁇ 6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2- spiro[3.3]heptyl ⁇ carbonyl)benzonitrile (Compound 128); [4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl] ⁇ 6-[3-methyl-1-(o-to-to-to-to-pyrazolyl]-2-aza-2- spiro[3.3]heptyl ⁇ carbonyl)benzonitrile (Compound 128); [4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl] ⁇
  • the administration of the compound transiently increases the level of 2-AG in the brain of the subject (e.g., within about 30 minutes after the oral administration of the compound to the subject). In some embodiments, the administration of the compound transiently increases the level of 2-AG in the brain of the subject. In some embodiments, the half-life of the transient increase of the 2-AG in the brain of the subject is less than twice the half-life of the compound in the blood plasma of the subject.
  • FIG.1A is a bar graph showing both the plasma and brain concentrations of a Reversible Selective MAGL Inhibitor in a murine model.
  • FIG.1B is a bar graph showing 2-AG measurement in the brain of a murine model after administration of a Reversible Selective MAGL Inhibitor.
  • FIG.2 is a scatter plot graph of the 2-AG concentration at varying brain concentrations of a Reversible Selective MAGL Inhibitor in a murine model.
  • FIG.3A is a graph showing the brain concentration after the administration of Compound 74 and a comparator compound JZL-184 in a mouse model.
  • FIG.3B is a graph showing the corresponding brain concentration of 2-AG after the administration of Compound 74 and a comparator compound JZL-184 in the animal model.
  • the compound is a Reversible MAGL Inhibitor Compound.
  • the compound is a Selective MAGL Inhibitor Compound.
  • the compound is both a Reversible MAGL Inhibitor Compound and a Selective MAGL Inhibitor Compound.
  • the endocannabinoid system consisting of cannabinoid receptors (CB1 and CB2), endocannabinoids (such as anandamide and 2- arachidonoylglycerol—2-AG), and enzymes involved in their synthesis and degradation, plays a crucial role in regulating neuronal excitability and seizure activity. Dysregulation of the endocannabinoid system has been implicated in epilepsy, with reduced levels of endocannabinoids found in epileptic brain tissue.
  • Monoacylglycerol Lipase MALM is the primary enzyme responsible for the degradation of 2-AG, the major endocannabinoid with potent anticonvulsant properties.
  • MAGL inhibitors offer a unique mechanism of action for modulating neuronal hyperexcitability and reducing seizure frequency, as a potential therapeutic strategy for effective seizure control with reduced adverse effects.
  • Targeting MAGL may help reduce the risk of unwanted psychoactive effects associated with non-selective cannabinoid agonists, making MAGL inhibitors potentially safer and more tolerable for epilepsy patients.
  • the endocannabinoid system comprising cannabinoid receptors (CB1 and CB2), endocannabinoids (such as anandamide and 2-arachidonoylglycerol), and enzymes involved in their synthesis and degradation, plays a crucial role in regulating neuronal excitability and seizure activity. Dysregulation of the endocannabinoid system has been implicated in epilepsy, with reduced levels of endocannabinoids observed in epileptic brain tissue.
  • MAGL is the primary enzyme responsible for the degradation of 2- arachidonoylglycerol, a major endocannabinoid with potent anticonvulsant properties. Inhibition of MAGL leads to increased levels of 2-arachidonoylglycerol, which, in turn, activates CB1 receptors, resulting in the suppression of excitatory neurotransmission and decreased neuronal excitability.
  • the endocannabinoid tone can be elevated, promoting a more favorable balance between excitatory and inhibitory signaling, thereby reducing seizure activity.
  • MAGL inhibition offers the advantage of selectively targeting the endocannabinoid system within specific brain regions or circuits involved in epileptic activity. Unlike systemic administration of exogenous cannabinoids, MAGL inhibitors can be designed to act locally, minimizing off-target effects on non-epileptic brain regions. This targeted approach may help to reduce the risk of unwanted psychoactive effects associated with non-selective cannabinoid agonists, making MAGL inhibitors potentially safer and more tolerable for epilepsy patients. [00027] In addition to their anticonvulsant properties, endocannabinoids have been shown to exert neuroprotective effects in various preclinical models of epilepsy.
  • MAGL inhibition represents a promising therapeutic approach for epilepsy by modulating the endocannabinoid system.
  • endocannabinoids particularly 2-arachidonoylglycerol
  • MAGL inhibitors can potentially restore the balance between excitatory and inhibitory signaling, reduce neuronal hyperexcitability, and exert neuroprotective effects.
  • Reversible MAGL (Monoacylglycerol Lipase) inhibition offers several advantages for epilepsy treatment compared to irreversible inhibition or other therapeutic approaches. These advantages include one or more of the following embodiments.
  • the inventions disclosed herein are based in part on the Applicant discovery of the use of reversible Selective MAGL Inhibitor Compounds to transiently increase the level of 2-AG in the brain.
  • the administration of a reversible Selective MAGL Inhibitor Compound increases the level of 2-AG in the brain of a subject with a half-life that is within twice the half-life of the blood plasma half-life of the reversible Selective MAGL Inhibitor Compound.
  • the use of a reversible Selective MAGL Inhibitor Compound of Formula (I-A), Formula (I-B), Formula (I-B-1), Formula (I-B-2), Formula (II) or Formula (III) is disclosed, for increasing the level of 2-AG in the brain of a subject with a half-life that is less than twice the corresponding blood plasma half- life for the reversible Selective MAGL Inhibitor Compound in the subject.
  • a method of treatment comprises administering a therapeutically effective amount of a compound that is a Reversible MAGL Inhibitor and a Selective MAGL Inhibitor to a patient in need thereof.
  • methods of treatment are provided.
  • the disclosure provides certain compounds of Formula (I-A) that are both a Selective MAGL Inhibitor Compound and a Reversible MAGL Inhibitor Compound as defined herein, or a pharmaceutically acceptable salt thereof: wherein A 1 is an aryl or heteroaryl optionally substituted with one or more Ra; each Ra is independently halogen, cyano, lower alkyl optionally substituted with one or more halogen, cycloalkyl, aminoalkyl, carboxy, carboxamide, or -OR 6 ; R 6 is hydrogen, lower alkyl or lower cycloalkyl optionally substituted with one or more halogen; V is selected from each p is independently 0, 1, 2, 3 or 4; each Rv is independently hydrogen, halogen, or alkyl optionally substituted with one or more halogen; W is -A 2 -, -C(O)-, C(O)-A 2 -, -C(O)N(R 10 )
  • methods of treatment comprise the administration or use of a compound that is both a Selective MAGL Inhibitor Compound and a Reversible MAGL Inhibitor Compound of Formula (I-A), wherein A 1 is a 6-member aryl or heteroaryl ring comprising at least one nitrogen; A 2 is a 5-member heteroaryl ring comprising at least one nitrogen heteroatom, and B is a 5- or 6- member aryl or B is a 5- or 6- member heteroaryl ring comprising at least one nitrogen atom, wherein each heteroaryl ring in A 1 , A 2 and B comprises one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • a 1 is a 6-member aryl or heteroaryl ring comprising at least one nitrogen
  • a 2 is a 5-member heteroaryl ring comprising at least one nitrogen heteroatom
  • B is a 5- or 6- member aryl or B is a 5- or 6- member heteroaryl ring comprising at least one nitrogen atom
  • a 1 in Formula (I-A) is a 6-member aryl or heteroaryl optionally substituted with one or more R a .
  • a 1 in Formula (I-A) is phenyl optionally substituted with one or more R a .
  • a 1 in Formula (I-A) is pyridine optionally substituted with one or more R a .
  • a 1 in Formula (I-A) is phenyl optionally substituted with one or more R a .
  • Each R a substitution of A 1 of Formula (I-A) can be the same or different.
  • Each R a in Formula (I-A) is independently halogen, cyano, lower alkyl optionally substituted with one or more halogen, cycloalkyl, aminoalkyl, carboxy, carboxamide, or -OR 6 ; and each R 6 in Formula (I-A) is independently hydrogen, lower alkyl or lower cycloalkyl optionally substituted with one or more halogen.
  • the halogen in Ra in Formula (I-A) is F or Cl.
  • the halogen in Ra in Formula (I-A) is F.
  • the halogen in Ra in Formula (I-A) is F or Cl.
  • the lower alkyl in Ra in Formula (I-A) is (C 1 -C 4 ) alkyl. In some embodiments, the lower alkyl in Ra in Formula (I-A) is methyl optionally substituted with one or more F. In some embodiments, R a in Formula (I-A) is CHF 2 , CH 2 F, CF 3 - cylopropyl, aminoalkyl (including azridinyl), carboxy, carboxamide, formamide, and amide. In some embodiments, cycloalkyl in R a in Formula (I-A) is cyclopropyl.
  • R a in Formula (I-A) is -NRxCORy or -CONRx or NRxCO, wherein Rx and Ry are each independently hydrogen or lower alkyl.
  • R a in Formula (I-A) is - NRxCORy or -CONRx or NRxCO, wherein Rx and Ry are each independently (C 1 -C 4 ) alkyl or hydrogen.
  • R a in Formula (I-A) is -NRxCORy or -CONRx or NRxCO, wherein Rx and Ry are each independently methyl.
  • R a in Formula (I-A) is -NRxCORy or -CONRx or NRxCO, wherein Rx and Ry are each independently hydrogen.
  • V in Formula (I-A) is , where n and each Rv is as defined above. In some embodiments, V in Formula (I-A) is where n and each Rv is as defined above. In some embodiments, V in Formula (I-A) is . In some embodiments, V in Formula (I-A) is . In some embodiments, V in Formula (I-A) is In some embodiments, V in Formula (I- A) is .
  • V in Formula (I-A) is where in Rv is as defined herein with respect to Formula (I-A).
  • each Rv in Formula (I-A) is independently hydrogen, halogen, or alkyl optionally substituted with one or more halogen.
  • one or more Rv in Formula (I-A) is hydrogen.
  • one or more Rv in Formula (I-A) is F or Cl.
  • one or more Rv in Formula (I-A) is F.
  • one or more Rv in Formula (I-A) is alkyl optionally substituted with one or more F.
  • one or more Rv in Formula (I-A) is lower alkyl optionally substituted with one or more F. In some embodiments, one or more Rv in Formula (I-A) is (C 1 -C 4 ) alkyl optionally substituted with one or more F. In some embodiments, one or more Rv in Formula (I-A) is CF 3 . In some embodiments, each Rv in Formula (I-A) is -O-R v2 where R v2 is hydrogen or alkyl optionally substituted with one or more halogen. In some embodiments, each Rv in Formula (I- A) is -O-R v2 where R v2 is hydrogen or lower alkyl optionally substituted with one or more halogen.
  • each Rv in Formula (I-A) is -O-R v2 where R v2 is hydrogen or lower alkyl optionally substituted with one or more F. In some embodiments, each Rv in Formula (I-A) is -O-R v2 where R v2 is hydrogen. In some embodiments, each Rv in Formula (I- A) is -O-R v2 where R v2 is lower alkyl optionally substituted with one or more halogen. In some embodiments, each Rv in Formula (I-A) is F. In some embodiments, each Rv in Formula (I-A) is methyl optionally substituted with one or more F. In some embodiments, each Rv in Formula (I-A) is methyl.
  • each Rv in Formula (I-A) is -O-R v2 where R v2 is (C 1 -C 4 ) alkyl optionally substituted with one or more halogen. In some embodiments, each Rv in Formula (I-A) is -O-R v2 where R v2 is (C 1 -C 4 ) alkyl optionally substituted with one or more F. In some embodiments, each Rv in Formula (I-A) is -O-R v2 where R v2 is methyl optionally substituted with one or more F. [00039] In some embodiments, each n with respect to Rv in Formula (I-A) is 0, 1, 2, 3 or 4.
  • each n with respect to Rv in Formula (I-A) is 0. In some embodiments, each n with respect to Rv in Formula (I-A) is 1. In some embodiments, each n with respect to Rv in Formula (I-A) is 2. In some embodiments, each n with respect to Rv in Formula (I-A) is 3. In some embodiments, each n with respect to Rv in Formula (I-A) is 4.
  • V in Formula (I-A) is , wherein Rv is halogen, lower alkyl optionally substituted with one or m ore halogen, or -O-R v2 where R v2 is (C 1 -C 4 ) alkyl optionally substituted with one or more halogen.
  • V in Formula (I-A) is , wherein Rv is F, (C 1 -C 4 ) alkyl optionally substituted with one or more F, or -O-R v2 where R v2 is methyl optionally substituted with one or more halogen.
  • V in Formula (I-A) is , wherein Rv is F, methyl optionally substituted with one or more F, or -O-R v2 where R v2 is methyl optionally substituted with one or more halogen. In some embodiments, V in Formula (I-A) is wherein Rv is F, methyl, ethyl, -CF 3, or -O-R v2 where R v2 is methyl optionally substituted with one or more halogen. [00041] In some embodiments, W in Formula (I-A) is A 2 , wherein A 2 is as defined above.
  • W in Formula (I-A) is -C(O)- or -C(O)N(R 10 )-, wherein R 10 is as defined above with respect to Formula (I-A). In some embodiments, W in Formula (I-A) is -C(O)-. In some embodiments, W in Formula (I-A) is -C(O)N(R 10 )-, wherein R 10 is as defined above with respect to Formula (I-A).
  • W in Formula (I-A) is A 2
  • W in Formula (I-B) is A, wherein A or A 2 is a 5-member heteroaryl comprising one or more heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with one or more R 30 as defined above.
  • a or A 2 is a 5-member heteroaryl comprising one or more heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with one or more R 30 as defined above.
  • W in Formula (I-A) or Formula (I-B) is a 5-member heteroaryl comprising one or more nitrogen heteroatoms and optionally further comprising one or more additional heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with one or more R 30 as defined above.
  • W in Formula (I-A) or Formula (I-B) is a 5-member heteroaryl comprising one or more nitrogen heteroatoms and optionally further comprising one or two additional heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with one or more R 30 as defined above.
  • W in Formula (I-A) or Formula (I-B) is selected from the group consisting of: S and wherein R 30 is as defined herein.
  • a 2 in Formula (I-A) is a 5-member heteroaryl ring optionally substituted with one or more R 30 , wherein R 30 is (C 1 -C 4 ) alkyl.
  • a 2 in Formula (I-A) is a 5-member heteroaryl ring optionally substituted with one or more R 30 , wherein R 30 is methyl.
  • each R 10 in Formula (I-A) can be the same or different.
  • each R 10 in Formula I-A is hydrogen or (C 1 -C 4 ) alkyl.
  • one or more R 10 in Formula I-A is hydrogen.
  • one or more R 10 in Formula I-A is (C 1 -C 4 ) alkyl.
  • one or more R 10 in Formula I-A is methyl.
  • B in Formula (I-A) is 5- or 6-member aryl or heteroaryl optionally substituted with one or more R b ; and each R b is independently halogen, cyano, lower alkyl optionally substituted with one or more halogen, cycloalkyl, aminoalkyl, carboxy, carboxamide, or -OR 6 ; and R 6 is hydrogen, lower alkyl or lower cycloalkyl optionally substituted with one or more halogen.
  • B in Formula (I-A) is phenyl or 5- or 6-member heteroaryl comprising one or more heteroatoms selected from N, O and S, wherein the B group is optionally substituted with one or more R b ; and each R b is independently halogen, cyano, (C 1 - C 4 ) alkyl optionally substituted with one or more halogen, (C 3 -C 6 )cycloalkyl, 3-6 member heterocycloalkyl, aminoalkyl, carboxy, carboxamide, or -OR 6 ; and R 6 is hydrogen, (C 1 -C 4 )alkyl or (C 3 -C 6 )cycloalkyl optionally substituted with one or more halogen.
  • any one or more halogen within the B group in Formula (I-A) is F.
  • B in Formula (I-A) is phenyl optionally substituted with one or more R b ; and each R b is independently F, Cl, cyano, (C 1 -C 4 ) alkyl optionally substituted with one or more F or Cl, (C 3 -C 6 )cycloalkyl, 3-6 member heterocycloalkyl, aminoalkyl, carboxy, carboxamide, or -OR 6 ; and R 6 is hydrogen, (C 1 -C 4 )alkyl or (C 3 -C 6 )cycloalkyl optionally substituted with one or more F or Cl.
  • B in Formula (I-A) is 5-member heteroaryl comprising one or more heteroatoms selected from N, O and S, optionally substituted with one or more R b ; and each R b is independently F, Cl, cyano, (C 1 -C 4 ) alkyl optionally substituted with one or more F or Cl, (C 3 -C 6 )cycloalkyl, 3-6 member heterocycloalkyl, aminoalkyl, carboxy, carboxamide, or - OR 6 ; and R 6 is hydrogen, (C 1 -C 4 )alkyl or (C 3 -C 6 )cycloalkyl optionally substituted with one or more F or Cl.
  • B in Formula (I-A) is 5-member heteroaryl comprising nitrogen and 0, 1 or 2 additional heteroatoms selected from N, O and S, optionally substituted with one or more R b ; and each R b is independently F, Cl, cyano, (C 1 -C 4 ) alkyl optionally substituted with one or more F or Cl, (C 3 -C 6 )cycloalkyl, 3-6 member heterocycloalkyl, aminoalkyl, carboxy, carboxamide, or -OR 6 ; and R 6 is hydrogen, (C 1 -C 4 )alkyl or (C 3 - C 6 )cycloalkyl optionally substituted with one or more F or Cl.
  • B in Formula (I-A) is 6-member heteroaryl comprising one or more heteroatoms selected from N, O and S, optionally substituted with one or more R b ; and each R b is independently F, Cl, cyano, (C 1 -C 4 ) alkyl optionally substituted with one or more F or Cl, (C 3 -C 6 )cycloalkyl, 3-6 member heterocycloalkyl, aminoalkyl, carboxy, carboxamide, or - OR 6 ; and R 6 is hydrogen, (C 1 -C 4 )alkyl or (C 3 -C 6 )cycloalkyl optionally substituted with one or more F or Cl.
  • B in Formula (I-A) is 6-member heteroaryl comprising nitrogen and 0, 1 or 2 additional heteroatoms selected from N, O and S, optionally substituted with one or more R b ; and each R b is independently F, Cl, cyano, (C 1 -C 4 ) alkyl optionally substituted with one or more F or Cl, (C 3 -C 6 )cycloalkyl, 3-6 member heterocycloalkyl, aminoalkyl, carboxy, carboxamide, or -OR 6 ; and R 6 is hydrogen, (C 1 -C 4 )alkyl or (C 3 - C 6 )cycloalkyl optionally substituted with one or more F or Cl.
  • B in Formula (I-A) is substituted with 0, 1, 2, 3, 4 or 4 R b that are each the same or different from each other.
  • one or more R b in Formula (I-A) is F.
  • one or more R b in Formula (I-A) is Cl.
  • one or more R b in Formula (I-A) is -CN.
  • one or more R b in Formula (I-A) is (C 1 -C 4 ) alkyl optionally substituted with one or more F or Cl.
  • one or more R b in Formula (I-A) is (C 1 -C 4 ) alkyl optionally substituted with one or more F.
  • one or more R b in Formula (I-A) is methyl optionally substituted with one or more F or Cl. In some embodiments, one or more R b in Formula (I-A) is methyl optionally substituted with one or more F. In some embodiments, one or more R b in Formula (I-A) is (C 3 -C 6 )cycloalkyl. In some embodiments, one or more R b in Formula (I-A) is cyclopropyl. In some embodiments, one or more R b in Formula (I-A) is cyclobutyl. In some embodiments, one or more R b in Formula (I-A) is cyclohexyl.
  • one or more R b in Formula (I-A) is a 3-member heterocycloalkyl group comprising an O, N or S heteroatom. In some embodiments, one or more R b in Formula (I-A) is a 4-member heterocycloalkyl group comprising one or more O, N or S heteroatoms. In some embodiments, one or more R b in Formula (I-A) is a 5-member heterocycloalkyl group comprising one or more O, N or S heteroatoms. In some embodiments, one or more R b in Formula (I-A) is a 6-member heterocycloalkyl group comprising one or more O, N or S heteroatoms.
  • one or more R b in Formula (I-A) is an aminoalkyl. In some embodiments, one or more R b in Formula (I-A) is carboxy group. In some embodiments, one or more R b in Formula (I-A) is OR 6 , and R 6 is hydrogen, (C 1 -C 4 )alkyl or (C 3 -C 6 )cycloalkyl optionally substituted with one or more F or Cl.
  • the disclosure provides a compound of Formula (I-B) or a pharmaceutically acceptable salt thereof: ormu a ( - ), wherein n is 1, 2, 3, 4 or 5; each R a is independently halogen, cyano, lower alkyl optionally substituted with one or more halogen, -OR 6 , amine, amide, or ester, R 6 is hydrogen, lower alkyl or cycloalkyl optionally substituted with one or more halogen; W is A, -C(O)-, or -C(O)N(R 10 )-; A is aryl or heteroaryl each optionally substituted with one or more R 30 ; each R 30 is independently lower alkyl optionally substituted with one or more halogen; R 10 is hydrogen or lower alkyl; m is 1, 2, 3, 4 or 5; and each R b is independently halogen, or lower alkyl optionally substituted with one or more halogen.
  • compounds can be a compound of Formula (I-B), wherein n is 1, 2 or 3 and each Ra is independently halogen, cyano, lower alkyl optionally substituted with one or more halogen, or -OR 6 ; R 6 is hydrogen, lower alkyl or cycloalkyl optionally substituted with one or more halogen.
  • n is 1, 2 or 3 and each Ra is independently F or Cl, cyano, (C 1 -C 4 )alkyl optionally substituted with one or more F, or -OR 6 ; R 6 is hydrogen, (C 1 -C 4 )alkyl or cyclopropyl optionally substituted with one or more F.
  • the disclosure provides a compound of Formula (I-B) or a pharmaceutically acceptable salt thereof, wherein: n is 1, 2, or 3; each Ra is independently halogen, cyano, lower alkyl optionally substituted with one or more halogen, or -OR 6 ; R 6 is hydrogen, lower alkyl or lower cycloalkyl optionally substituted with one or more halogen; W is A, -C(O)-, -C(O)-A-, or -C(O)N(R 10 )-; R 10 is hydrogen or lower alkyl; A is a 5-member heteroaryl ring optionally substituted with one or more R 30 ; R 30 is lower alkyl; m is 1, or 2; and each R b is independently halogen, or lower alkyl optionally substituted with one or more halogen.
  • W is a 5-member heteroaryl ring comprising at least one nitrogen, such as a triazole, imidazole, pyrazole, or an oxadiazole.
  • one or more of the lower alkyl groups in Ra, Rv, R 6 , R 10 , R 30 and R b can independently be methyl.
  • a compound is a compound of Formula (I-B), wherein each Ra is independently Cl, F, CN , cyano, methyl, or -OR 6 ; R 6 is hydrogen, (C 1 -C 4 )alkyl optionally substituted with one or more F or cyclopropyl; W is -A-, -C(O)-, or -C(O)N(R 10 )-; R 10 is hydrogen or methyl; A is a 5-member heteroaryl ring optionally substituted with one or more R 30 ; R 30 is (C 1 -C 4 )alkyl; m is 1, or 2; and each R b is independently halogen, or (C 1 -C 4 )alkyl optionally substituted with one or more F.
  • a compound is a compound of Formula (I-B) wherein R 30 is methyl; and each R b is independently halogen, or methyl optionally substituted with one or more F.
  • a compound is a compound of Formula (I-B) wherein A is pyrazole, imidazole, or triazole, each optionally substituted with one methyl.
  • a compound is a compound of Formula (I-B) wherein A is oxadiazole.
  • a compound is a compound of Formula (I-B), wherein A is pyrazole substituted with one methyl.
  • a compound is a compound of Formula (I- B), wherein one Ra is -OR 6 .
  • compounds of Formula (I-A) of Formula (I-B) can be a compound of Formula (I-B-1), or pharmaceutically acceptable salt thereof: ormua ( - - ), wherein R 1 is hydrogen or halogen; R 3 is hydrogen, halogen, or lower alkyl optionally substituted with one or more halogen; R 5 is hydrogen, halogen, lower alkoxy or lower alkyl each optionally substituted with one or more halogen; R 6 is hydrogen, lower alkyl or cycloalkyl optionally substituted with one or more halogen; and W is A, -C(O)-, or -C(O)N(R 10 )-; A is aryl or heteroaryl each optionally substituted with one or more R 30 ; each R 30 is independently lower alkyl optionally substituted with one or more halogen; R 10 is
  • a compound is a compound of Formula (I-B-1) wherein R 1 is hydrogen, -CN, Cl or F.
  • R 6 is hydrogen, (C 1 -C 4 )alkyl or cyclopropyl optionally substituted with one or more F.
  • a compound is a compound of Formula (I-B-1) wherein R 1 is hydrogen, -CN, Cl or F and R 6 is hydrogen, (C 1 -C 4 )alkyl or cyclopropyl optionally substituted with one or more F.
  • R 3 is hydrogen, F, or methyl optionally substituted with one or more halogen.
  • a compound is a compound of Formula (I-B-1) wherein R 1 is hydrogen, -CN, Cl or F; R 6 is hydrogen, (C 1 - C 4 )alkyl or cyclopropyl optionally substituted with one or more F; and R 3 is hydrogen, F, or methyl optionally substituted with one or more halogen.
  • a compound is a compound of Formula (I-B-1) wherein R 1 is hydrogen, -CN, Cl or F; R 6 is hydrogen, (C 1 -C 4 )alkyl or cyclopropyl optionally substituted with one or more F; R 3 is hydrogen, F, or methyl optionally substituted with one or more halogen; and R 5 is hydrogen.
  • a compound is a compound of Formula (I-B-1) wherein R 1 is Cl, F or -CN and R 6 is hydrogen. In some embodiments, a compound is a compound of Formula (I-B-1) wherein R 1 is F. In some embodiments, a compound is a compound of Formula (I-B-1) wherein R 1 is Cl, F or -CN and R 3 , R 5 and R 6 are each hydrogen. In some embodiments, a compound is a compound of Formula (I- B-1) wherein R 1 is Cl, F or -CN; R 3 is hydrogen, methyl or F; R 5 is hydrogen, methyl or F; and R 6 is hydrogen.
  • a compound is a compound of Formula (I- B-1) wherein R 1 is F; R 3 is hydrogen, methyl or F; R 5 is hydrogen; and R 6 is hydrogen.
  • a compound is a compound of Formula (I- B-1) wherein R 1 is F; R 3 is hydrogen; R 5 is hydrogen or F; and R 6 is hydrogen.
  • a compound is a compound of Formula (I- B-1) wherein R 1 is hydrogen; R 3 is hydrogen or F; R 5 is hydrogen; and R 6 is hydrogen.
  • a compound is a compound of Formula (I- B-1) wherein R 1 is F or -CN; R 3 is hydrogen or F; R 5 is hydrogen; and R 6 is hydrogen.
  • a compound is a compound of Formula (I- B-1) wherein R 1 and R 6 are each hydrogen.
  • a compound is a compound of Formula (I- B-1) wherein R 1 is F and R 6 is hydrogen.
  • a compound is a compound of Formula (I- B-1) wherein R 1 is F, R 6 is hydrogen and at least one of R 3 and R 5 is hydrogen.
  • a compound is a compound of Formula (I- B-1) wherein R 1 is F, R 6 is hydrogen, and R 3 and R 5 are each hydrogen.
  • a compound is a compound of Formula (I- B-1) wherein R 1 is F, R 6 is hydrogen and at least one of R 3 and R 5 is hydrogen and at least one of R 3 and R 5 is F or methyl.
  • a compound is a compound of Formula (I-B-1) wherein W is A and A is 5-member aryl or 5-member heteroaryl wherein each A is optionally substituted with one or more R 30 ; and each R 30 is independently lower alkyl optionally substituted with one or more halogen.
  • a compound is a compound of Formula (I-B-1) wherein W is A and A is 5-member heteroaryl comprising at least one nitrogen heteroatom wherein each A is optionally substituted with one or more R 30 ; and each R 30 is independently (C 1 -C 4 ) alkyl optionally substituted with one or more halogen.
  • a compound is a compound of Formula (I-B-1) wherein W is A and A is 5-member heteroaryl comprising at least one nitrogen heteroatom wherein each A is optionally substituted with one or more R 30 ; and each R 30 is independently F or methyl optionally substituted with one or more F.
  • compounds of Formula (I-A) or Formula (I-B) can be a compound of Formula (I-B-2), or pharmaceutically acceptable salt thereof:
  • a compound is a compound of Formula (I-B-2) wherein R 3 is hydrogen, Cl or F.
  • a compound is a compound of Formula (I-B-2) wherein R 3 is F. In some embodiments, a compound is a compound of Formula (I-B-2) wherein R 52 is (C 1 -C 4 )alkyl optionally substituted with one or more halogen, or cyclopropyl. In some embodiments, a compound is a compound of Formula (I-B-2) wherein R 3 is F and R 52 is (C 1 - C 4 )alkyl optionally substituted with one or more halogen, or cyclopropyl.
  • a compound is a compound of Formula (I-B-2) wherein R 52 is (C 1 -C 4 )alkyl optionally substituted with one or more F, or cyclopropyl.
  • a compound is a compound of Formula (I-B-2) wherein R 3 is F and R 52 is (C 1 -C 4 )alkyl optionally substituted with one or more F, or cyclopropyl.
  • a compound is a compound of Formula (I-B-2) wherein R 52 is selected from the group consisting of: methyl, ethyl, propyl optionally substituted with one or more F.
  • a compound is a compound of Formula (I-B-2) wherein R 3 is F and R 52 is selected from the group consisting of: methyl, ethyl, propyl optionally substituted with one or more F.
  • a compound is a compound of Formula (I-B-2) wherein R 52 is selected from the group consisting of: methyl, ethyl, isopropyl, -CH 2 -CF 3 and cyclopropyl.
  • a compound is a compound of Formula (I-B-2) wherein R 3 is F and R 52 is selected from the group consisting of: methyl, ethyl, isopropyl, -CH 2 -CF 3 and cyclopropyl.
  • a compound is a compound of Formula (I-B-2) wherein W is A and A is 5-member aryl or 5-member heteroaryl wherein each A is optionally substituted with one or more R 30 ; and each R 30 is independently lower alkyl optionally substituted with one or more halogen.
  • a compound is a compound of Formula (I-B-2) wherein W is A and A is 5-member heteroaryl comprising at least one nitrogen heteroatom wherein each A is optionally substituted with one or more R 30 ; and each R 30 is independently (C 1 -C 4 ) alkyl optionally substituted with one or more halogen.
  • a compound is a compound of Formula (I-B-2) wherein W is A and A is 5-member heteroaryl comprising at least one nitrogen heteroatom wherein each A is optionally substituted with one or more R 30 ; and each R 30 is independently F or methyl optionally substituted with one or more F.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein W is A, and A is an aryl or heteroaryl optionally substituted with one or more R 30 , and R 30 is (C 1 -C 4 )alkyl optionally substituted with one or more halogen.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein A is a 5-member heteroaryl optionally substituted with one or more (C 1 -C 4 )alkyl optionally substituted with one or more halogen.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein A is a 5-member heteroaryl comprising one or more nitrogen heteroatoms and optionally substituted with one or more methyl.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein W is selected from the group consisting of: imidazole, prazole, triazole and oxadiazole each optionally substituted with one or more lower alkyl.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein W is selected from the group consisting of: imidazole, prazole, triazole and oxadiazole each optionally substituted with one or more methyl.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I- B-1) or Formula (I-B-2), wherein W is selected from the group consisting of A1, A2, A3, A4, A5, A6 and A7 as shown below, wherein R 30 , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 and R 39 are each independently hydrogen or lower alkyl: , .
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein W is selected from the group consisting of A1, A2, A3, A4, A5, and A6 as shown above, wherein R 30 , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 and R 39 are each independently hydrogen or methyl.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein W is selected from the group consisting of A1, A2, A3, A4, A5, and A6 as shown above, wherein R 30 , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 and R 39 are each independently hydrogen or methyl.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein W is A1 and R 30 is hydrogen or methyl.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein W is A1 and R 30 is hydrogen.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein W is A1 and R 30 is methyl.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein W is A2 and R 32 and R 33 is hydrogen or methyl.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein W is A2 and one of R 32 and R 33 is hydrogen and one of R 32 and R 33 is methyl.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein W is A2 and R 32 is methyl and R 33 is hydrogen.
  • a compound is a compound of Formula (I-A), Formula (I- B), Formula (I-B-1) or Formula (I-B-2), wherein W is A2 and R 32 is hydrogen and R 33 is methyl.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I- B-1) or Formula (I-B-2), wherein W is A2 and R 32 is hydrogen and R 33 is hydrogen.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein W is A3 and R 34 is hydrogen or methyl.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein W is A3 and R 34 is hydrogen.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein W is A1 and R 34 is methyl.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein W is A4 and one of R 36 and R 37 is hydrogen and one of R 36 and R 37 is methyl.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein W is A4 and R 36 is methyl and R 37 is hydrogen.
  • a compound is a compound of Formula (I-A), Formula (I- B), Formula (I-B-1) or Formula (I-B-2), wherein W is A4 and R 36 is hydrogen and R 37 is methyl.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I- B-1) or Formula (I-B-2), wherein W is A4 and R 36 is hydrogen and R 37 is hydrogen.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein W is A5.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein W is A6 and one of R 38 and R 39 is hydrogen and one of R 38 and R 39 is methyl.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein W is A6 and R 38 is methyl and R 39 is hydrogen.
  • a compound is a compound of Formula (I-A), Formula (I- B), Formula (I-B-1) or Formula (I-B-2), wherein W is A6 and R 38 is hydrogen and R 39 is methyl.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I- B-1) or Formula (I-B-2), wherein W is A6 and R 38 is hydrogen and R 39 is hydrogen.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein at least one of Ra is hydroxyl or (C 1 -C 4 )alkoxy optionally substituted with one or more halogen, and n is 1, 2 or 3.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein at least one of Ra is hydroxyl or (C 1 -C 4 )alkoxy optionally substituted with one or more F, and n is 1, 2 or 3.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein at least one of Ra is hydroxyl, (C 1 -C 4 )alkoxy or -O-(C 1 -C 6 )cycloalkyl each optionally substituted with one or more F, with the remaining Ra selected from the group consisting of halogen, methyl, and cyano; and n is 1, 2 or 3.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein at least one of Ra is hydroxyl, (C 1 -C 4 )alkoxy or -O-(cyclopropyl) each optionally substituted with one or more F, with the remaining Ra selected from the group consisting of halogen, methyl, and cyano; and n is 1, 2 or 3.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein at least one of Ra is hydroxyl, (C 1 -C 4 )alkoxy or -O-(cyclopropyl) each optionally substituted with one or more F, with the remaining Ra selected from the group consisting of Cl, F, methyl, and cyano; and n is 1, 2 or 3.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein W is A7.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein W is -C(O)-.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein W is -C(O)N(R 10 )-, and -R 10 is hydrogen.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein W is -C(O)N(R 10 )-, and -R 10 is methyl.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein W is -C(O)N(R 10 )-, and -R 10 is (C 1 -C 4 ) alkyl optionally substituted with F.
  • a compound is a compound of Formula (I-A), Formula (I-B), Formula (I-B-1) or Formula (I-B-2), wherein W is -C(O)N(R 10 )-, and -R 10 is lower alkyl optionally substituted with halogen.
  • compounds of Formula (I-A) or Formula (I-B) can be a compound of Formula (I-C), or pharmaceutically acceptable salt thereof: Formula (I-C) wherein: R 20 is lower alkyl; n is 1, 2, or 3; each R a is independently halogen, cyano, lower alkyl optionally substituted with one or more halogen, or -OR 6 ; W is as defined with respect to Formula (I-B); and R 6 is hydrogen, lower alkyl or lower cycloalkyl optionally substituted with one or more halogen.
  • a compound is a compound of Formula (I-C), wherein R 20 is (C 1 -C 4 )alkyl.
  • a compound is a compound of Formula (I-C), wherein R 20 is methyl.
  • a compound is a compound of Formula (I-C), wherein W is A7 and R 20 is methyl, each Ra is independently F, Cl, -CN, (C 1 -C 4 )alkyl optionally substituted with one or more F or Cl, or -OR 6 and R 6 is hydrogen, (C 1 -C 4 )alkyl or cyclopropyl optionally substituted with one or more F or Cl.
  • a compound is a compound of Formula (I-C), wherein n is 1, 2 or 3, W is A7 and R 20 is methyl, each Ra is independently F, Cl, -CN, methyl, or -OH.
  • a compound is a compound of Formula (I-C), wherein n is 2, W is A7 and R 20 is methyl, each Ra is independently F or -OH.
  • a compound is a compound of Formula (I-C), wherein at least one of Ra is hydroxyl or (C 1 -C 4 )alkoxy optionally substituted with one or more halogen, and n is 1, 2 or 3.
  • a compound is a compound of Formula (I-C), wherein at least one of Ra is hydroxyl or (C 1 -C 4 )alkoxy optionally substituted with one or more F, and n is 1, 2 or 3.
  • a compound is a compound of Formula (I-C), wherein at least one of Ra is hydroxyl, (C 1 -C 4 )alkoxy or -O-(C 1 -C 6 )cycloalkyl each optionally substituted with one or more F, with the remaining Ra selected from the group consisting of halogen, methyl, and cyano; and n is 1, 2 or 3.
  • a compound is a compound of Formula (I-C), wherein at least one of Ra is hydroxyl, (C 1 -C 4 )alkoxy or -O-(cyclopropyl) each optionally substituted with one or more F, with the remaining Ra selected from the group consisting of halogen, methyl, and cyano; and n is 1, 2 or 3.
  • a compound is a compound of Formula (I-C), wherein at least one of Ra is hydroxyl, (C 1 -C 4 )alkoxy or -O-(cyclopropyl) each optionally substituted with one or more F, with the remaining Ra selected from the group consisting of Cl, F, methyl, and cyano; and n is 2 or 3.
  • a compound is a compound of Formula (I-C), wherein at least one of Ra is hydroxyl, with the remaining Ra selected from the group consisting of F, methyl, and cyano; and n is 2 or 3.
  • the disclosure provides a compound of Formula (I-A) or Formula (I-B) that are also compounds of Formula (II) or a pharmaceutically acceptable salt thereof:
  • R 1 is halogen or cyano
  • R 3 is hydrogen, lower alkyl, or halogen
  • W is A, -C(O)-, or -C(O)N(R 10 )-
  • R 10 is hydrogen or lower alkyl
  • A is a 5-member heteroaryl ring optionally substituted with one or more R 30
  • R 20 is halogen or lower alkyl optionally substituted with one or more halogen
  • R 30 is lower alkyl optionally substituted with one or more halogen
  • R 26 is halogen or hydrogen.
  • a compound of Formula (I-A) or Formula (I-B) can be a compound of Formula (II) wherein R 1 is Cl, F or cyano; R 3 is hydrogen, F or methyl; R 10 is hydrogen or methyl; R 20 and R 30 are each independently methyl; and R 26 is F or hydrogen.
  • a compound of Formula (I) can be a compound of Formula (II) wherein R 1 is Cl, F or cyano; R 3 is hydrogen, F or methyl; R 10 is hydrogen or methyl; R 20 and R 30 are each independently methyl; and R 26 is hydrogen.
  • a compound of Formula (I) can be a compound of Formula (II) wherein W is -C(O)N(R 10 )- wherein R 10 is hydrogen or methyl and A is a 5-member heteroaryl ring comprising at least one nitrogen optionally substituted with one or more lower alkyl, the lower alkyl being optionally substituted with one or more halogen; and R 26 is hydrogen.
  • a compound of Formula (I) can be a compound of Formula (II) wherein R 20 and R 30 are each independently lower alkyl optionally substituted with one or more F and R 26 is hydrogen.
  • a compound of Formula (I) can be a compound of Formula (II) wherein R 20 is halogen or lower alkyl optionally substituted with one or more F; R 30 is lower alkyl optionally substituted with one or more F; and R 26 is hydrogen.
  • a compound of Formula (I) can be a compound of Formula (II) wherein R 20 is Cl, F or methyl optionally substituted with one or more F; R 30 is methyl optionally substituted with one or more F; and R 26 is hydrogen.
  • a compound of Formula (I-A) or Formula (I-B) can be a compound of Formula (II) wherein W is an amide optionally substituted with lower alkyl, carboxyl or 5-member heteroaryl ring comprising at least one nitrogen, such as a pyrazole, imidazole, triazole or oxadiazole, each optionally substituted with lower alkyl.
  • R 1 is Cl, F or CN in Formula (II); and R 26 is hydrogen.
  • R 3 is methyl; and R 26 is hydrogen.
  • R 3 is hydrogen; and R 26 is hydrogen.
  • R 3 is F; and R 26 is hydrogen.
  • a compound can be a compound of Formula (II) wherein W is pyrazole, imidazole, triazole or oxadiazole, each optionally substituted with methyl; R 1 is Cl, F or CN; R 3 is hydrogen, methyl or F; and R 26 is hydrogen.
  • a compound of Formula (I-A) or Formula (I-B) can be a compound of Formula (II) wherein the lower alkyl in R 1 , R 3 , and R 20 is methyl; and R 26 is hydrogen.
  • a compound of Formula (I) can be a compound of Formula (II) wherein R 10 is methyl; A is pyrazole, imidazole, triazole or oxadiazole each optionally substituted with methyl; and R 20 is methyl; and R 26 is hydrogen.
  • a compound of Formula (I) can be a compound of Formula (II) wherein W is pyrazole optionally substituted with one or more methyl; R 1 is the F; R 3 is H or F and R 20 is methyl; and R 26 is hydrogen.
  • a compound of Formula (I) can be a compound of Formula (II) wherein W is pyrazole optionally substituted with one or more methyl, R 1 is the F, R 3 is H and R 20 is methyl and R 26 is hydrogen.
  • a compound of Formula (I-A) or Formula (I-B) can be a compound of Formula (II) wherein the lower alkyl in R 1 , R 3 , and R 20 is methyl; and R 26 is F.
  • a compound of Formula (I) can be a compound of Formula (II) wherein R 10 is methyl; A is pyrazole, imidazole, triazole or oxadiazole each optionally substituted with methyl; and R 20 is methyl; and R 26 is F.
  • a compound of Formula (I) can be a compound of Formula (II) wherein W is pyrazole optionally substituted with one or more methyl; R 1 is the F; R 3 is H or F and R 20 is methyl; and R 26 is F.
  • a compound of Formula (I) can be a compound of Formula (II) wherein W is pyrazole optionally substituted with one or more methyl, R 1 is the F, R 3 is H and R 20 is methyl and R 26 is F.
  • W is a 5-member heteroaryl ring comprising at least one nitrogen, such as a pyrazole.
  • R 1 is Cl, F or CN.
  • R 3 is H.
  • R 3 is F.
  • the lower alkyl in each of Ra, R 6 , R 10 , R 30 and R b can independently be methyl.
  • W is pyrazole optionally substituted with one or more methyl, R 1 is the F, R 3 is H or F and each of Ra, R 6 , R 10 , R 30 and Rb is methyl in a compound of Formula (II). In some embodiments, W is pyrazole optionally substituted with one or more methyl, R 1 is the F, R 3 is H and each of Ra, R 6 , R 10 , R 30 and Rb is methyl in a compound of Formula (II). [00086] In some embodiments, the compound of Formula (II) is selected from the group consisting of: , , , , , ,
  • the compound of Formula (II) is selected from the group consisting of: , , , , , ,
  • the resulting mixture was stirred at room temperature for 2h.
  • the reaction mixture was quenched by the addition of ice cold water (10 mL) and extracted by ethyl acetate (3x25 mL).
  • the organic layer was dried over sodium sulphate and concentrated under reduced pressure.
  • the crude material was purified by column chromatography using 5 % MeOH in DCM.
  • the disclosure provides methods of using a compound of Formula (III) or a pharmaceutically acceptable salt thereof: wherein R 3 is halogen; R 5 is -O-R 52 ; R 52 is lower alkyl or cycloalkyl, each optionally substituted with halogen, W is a 5-member heteroaryl ring optionally substituted with one or more R 30 ; R 30 is lower alkyl; R 20 is lower alkyl; and R 26 is hydrogen or halogen.
  • R 20 is methyl and R 26 is hydrogen or F in compounds of Formula (III).
  • R 20 is methyl and R 26 is hydrogen in compounds of Formula (III).
  • R 20 is methyl and R 26 is F.
  • W is a 5-member heteroaryl ring comprising at least one nitrogen, such as a pyrazole.
  • R 3 is F.
  • R 62 is lower alkyl or cycloalkyl.
  • the lower alkyl in R 20 , R 30 and R 62 can be methyl.
  • W is pyrazole optionally substituted with one or more methyl, and R 3 is the F.
  • W is pyrazole optionally substituted with one or more methyl
  • R 3 is the F
  • R 62 is methyl, ethyl, propyl or cyclopropyl each optionally substituted with one or more F
  • R 20 is methyl in a compound of Formula (III).
  • the compound of Formula (III) is selected from the group consisting of:
  • the compound of Formula (III) is selected from the group consisting of: [00094] In some embodiments, methods comprise use of a compound selected from the group consisting of:
  • the disclosure provides methods of using a compound of Formula (III) or a pharmaceutically acceptable salt thereof: Formula (III-A) wherein R 3 is halogen; R 62 is lower alkyl or cycloalkyl, each optionally substituted with halogen, W is a 5-member heteroaryl ring optionally substituted with one or more R 30 ; R 30 is lower alkyl; and R 20 is lower alkyl.
  • W is a 5-member heteroaryl ring comprising at least one nitrogen, such as a pyrazole.
  • R 3 is F.
  • R 62 is lower alkyl or cycloalkyl.
  • the lower alkyl in R 20 , R 30 and R 62 can be methyl.
  • W is pyrazole optionally substituted with one or more methyl, and R 3 is the F.
  • W is pyrazole optionally substituted with one or more methyl, and R 3 is the F, R 62 is methyl, ethyl, propyl or cyclopropyl each optionally substituted with one or more F, and R 20 is methyl in a compound of Formula (III-A).
  • V in Formula (I-A) is , where n and each Rv is as defined above, and the dashed line represents an optional double bond.
  • the dashed line represents an optional double bond.
  • the dashed line represents an optional double bond in Fomula (I-B-1) in Fomula (I-B-1) the dashed line represents an optional double bond.
  • the dashed line represents an optional double bond. In some embodiments, in Formula (II) the dashed line represents an optional double bond.
  • the compounds described herein can exist as salts, such as with pharmaceutically acceptable acids. Accordingly, such salts of the compounds described herein are included.
  • pharmaceutically acceptable salt is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic,
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • compositions [000101]
  • the present application is directed to a pharmaceutical composition comprising an active pharmaceutical ingredient.
  • the pharmaceutical composition comprises a compound as disclosed herein as the active pharmaceutical ingredient (API) and a pharmaceutically acceptable carrier comprising one or more excipients.
  • the pharmaceutical composition optionally further comprises an additional therapeutic compound (i.e., agent) with the pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be a medicament.
  • Pharmaceutically acceptable carriers include those known in the art. The choice of a pharmaceutically acceptable carrier can depend, for example, on the desired route of administration of the composition.
  • a pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, parenteral administration (e.g.
  • compositions comprising compounds of Formula (I-A), Formula (I-B), Formula (I-B-1), Formula (I-B-2), Formula (I-C), Formula (II), Formula (III) or pharmaceutically acceptable salts thereof can be formulated for oral administration.
  • a compound provided herein can be combined with suitable compendial excipients to form an oral unit dosage form, such as a capsule or tablet, containing a target dose of a compound of Formula (I-A), Formula (I-B), Formula (I-B-1), Formula (I-B-2), Formula (II), Formula (III).
  • the drug product can be prepared by first manufacturing the compound of Formula (I-A), Formula (I-B), Formula (I-B-1), Formula (I-B-2), Formula (I-C), Formula (II), Formula (III) as an active pharmaceutical ingredient (API), followed by roller compaction/milling with intragranular excipients and blending with extra granular excipients.
  • a Drug Product can contain the selected compound of Formula (I-A), Formula (I-B), Formula (I-B- 1), Formula (I-B-2), Formula (I-C), Formula (II), Formula (III) as the API and excipient components in a tablet in a desired dosage strength of Compound 1.
  • the blended material can be compressed to form tablets and then film coated.
  • the excipients can be selected from materials appropriate for inclusion in a pharmaceutical composition for an intended purpose and route of delivery including providing a desired manufacturing and stability properties and/or desired in vivo characteristics or other properties to the pharmaceutical composition.
  • the pharmaceutical composition can include a compound of Formula (I-A), Formula (I-B), Formula (I-B-1), Formula (I-B-2), Formula (I-C), Formula (II), Formula (III) as the API in combination with a filler (e.g., a form of microcrystalline cellulose), a dry binder or disintegrant (e.g., a cross-linked polymer), a glidant (e.g., colloidal silicon dioxide) and/or a lubricant (e.g., magnesium stearate).
  • a filler e.g., a form of microcrystalline cellulose
  • a dry binder or disintegrant e.g., a cross-linked polymer
  • a glidant e.g., colloidal silicon dioxide
  • a lubricant e.g., magnesium stearate
  • the pharmaceutical composition can comprise a material such as an extended release or disintegrant involved in carrying or transporting the API pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject, including materials to desirable control the absorption of the API in the intestine.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.
  • active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, (2) binders, (3) humectants, (4) disintegrating agents, (5) solution retarding agents, (6) absorption accelerators, (7) wetting agents, (8) absorbents, (9) lubricants, (10) complexing agents, and (11) coloring agents.
  • pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, (2) binders, (3) humectants, (4) disintegrating agents, (5) solution retarding agents, (6) absorption accelerators, (7) wetting agents, (8) absorbents, (9) lubricants, (10) complexing agents, and (11) coloring agents.
  • the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using suitable excipients.
  • compositions according to the present invention may contain conventional pharmaceutical carriers and/or auxiliary agents.
  • he pharmaceutical compositions according to the present invention may contain conventional carrier agents including a binder, a lubricant and/or a glidant selected from those products and materials generally used in pharmaceutical industry for preparation of pharmaceutical compositions for an intended route of administration.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • Liquid dosage forms useful for oral administration include pharmaceutically acceptable carriers and the active ingredient provided as a solid form for reconstitution prior to administration or as a liquid (e.g., solutions, suspensions, or emulsions).
  • a liquid dosage forms may contain inert diluents commonly used in the art.
  • formulations of pharmaceutically acceptable compositions for injection can include aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles suitable for the intended route of administration.
  • the pharmaceutical composition is formulated for parenteral administration.
  • the therapeutically effective amount of a pharmaceutical composition can be determined by human clinical trials to determine the safe and effective dose for a patient with a relevant diagnosis. It is generally understood that the effective amount of the compound may vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the pharmaceutical composition at a dose and dose interval determined to be safe and effective for the patient. [000110] The present disclosure includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention.
  • Pharmaceutically-acceptable salts include, for example, acid-addition salts and base- addition salts.
  • the acid that is added to a compound to form an acid-addition salt can be an organic acid or an inorganic acid.
  • a base that is added to a compound to form a base-addition salt can be an organic base or an inorganic base.
  • a pharmaceutically-acceptable salt is a metal salt, in some embodiments, a pharmaceutically-acceptable salt is an ammonium salt.
  • a pharmaceutically acceptable acid addition salt can exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared.
  • the source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
  • Methods of use [000111] The inventors have discovered inter alia compounds of Formula (I-A), Formula (I-B), Formula (II) and Formula (III) can modulate, e.g., inhibit monoacylglycerol lipase. Accordingly, in another aspect, the disclosure provides a method for inhibiting monoacylglycerol lipase (MAGL). Generally, the method comprises administering a compound of Formula (I-A), Formula (I-B), Formula (II) and Formula (III) to a cell, e.g., a cell expressing MAGL.
  • a cell e.g., a cell expressing MAGL.
  • administering to the cell can be in vitro or in vivo.
  • an effective amount of a compound of Formula (I-A), Formula (I-B), Formula (II) and Formula (III) can be administered to a subject for inhibiting MAGL.
  • methods of treatment are provided.
  • methods of treatment are provided.
  • a method of treating management of epilepsy or for the relief of the symptoms of epilepsy or epilepsy associated comprises administering a therapeutically effective amount of a compound of Formula (I-A) to a patient in need thereof.
  • methods of treatment are provided.
  • methods of treatment comprise the administration of a reversible MAGL inhibitor compound for the treatment of epilepsy.
  • a compound provided herein can be administered to the cell, e.g. cell expressing MAGL in vitro or ex vivo.
  • administering the compound to the cell means contacting the cell with the compound so that the compound is taken up by the cell.
  • the cell can be contacted with the compound in a cell culture e.g., in vitro or ex vivo, or the compound can be administrated to a subject, e.g., in vivo.
  • contacting or “contact” as used herein in connection with contacting a cell includes subjecting the cells to an appropriate culture media, which comprises a compound of Formula (I-A), Formula (I-B), Formula (I-B-1), Formula (I-B-2), Formula (II), Formula (III).
  • “contacting” or “contact” includes administering the compound, e.g., in a pharmaceutical composition to a subject via an appropriate administration route such that the compound contacts the cell in vivo.
  • the compound of Formula (I-A), Formula (I-B), Formula (I-B-1), Formula (I-B-2), Formula (I-C), Formula (II), Formula (III) can be administered to a cell in vivo for modulating MAGL, e.g., inhibiting MAGL. Accordingly, in some embodiments, a therapeutically effective amount of a compound of Formula (I-A), Formula (I-B), Formula (I-B- 1), Formula (I-B-2), Formula (I-C), Formula (II), Formula (III) can be administered to a subject for inhibiting monoacylglycerol lipase.
  • a therapeutically effective amount of a compound of Formula (I-A), Formula (I-B), Formula (I-B-1), Formula (I-B-2), Formula (I-C), Formula (II), Formula (III) can be administrated to a subject for treating a monoglycerol lipase mediated disease or disorder.
  • a MAGL-mediated disease or disorder is meant a disease or disorder wherein activity of MAGL is a cause of the disease or disorder. (See, e.g., Zanfirescu (Molecules 2021), Deng (Acta Pharm Sinica B, 2020), and Mulvihill (NIH Life Sci 2013)).
  • a method of treating epilepsy comprises administering a therapeutically effective amount of a reversible MAGL inhibitor to a patient in need thereof.
  • a method of treating epilepsy and related conditions comprises administering a therapeutically effective amount of a compound of Formula (I-A) to a patient in need thereof.
  • the disclosure provides methods of using including methods of treatment comprising the use of certain compounds that are both a Selective MAGL Inhibitor Compound and a Reversible MAGL Inhibitor Compound as defined herein, or a pharmaceutically acceptable salt thereof.
  • a subject can be one who has been previously diagnosed with or identified as suffering from or having a condition in need of treatment a MAGL-mediated disease or disorder or one or more complications related to such a condition, and optionally, have already undergone treatment for such a disease or disorder.
  • a subject can also be one who has not been previously diagnosed as having a MAGL-mediated disease or disorder or one or more complications related to such a disease or disorder.
  • a “subject in need” of treatment for a particular condition can be a subject having that condition, diagnosed as having that condition, or at risk of developing that condition.
  • the subject is human.
  • the subject is an experimental animal or animal substitute as a disease model.
  • administering and “subjected” are used interchangeably in the context of treatment of a disease or disorder.
  • the meaning of “administering” of a composition to a human subject shall be restricted to prescribing a controlled substance that a human subject will be administer to the subject by any technique (e.g., orally, inhalation, topical application, injection, insertion, etc.).
  • any technique e.g., orally, inhalation, topical application, injection, insertion, etc.
  • the “administering” of compositions includes both methods practiced on the human body and also the foregoing activities.
  • the term “administer” refers to the placement of a composition into a subject by a method or route which results in at least partial localization of the composition at a desired site such that desired effect is produced.
  • a compound or composition described herein can be administered by any appropriate route known in the art including, but not limited to, oral or parenteral routes, including intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), pulmonary, nasal, rectal, and topical (including buccal and sublingual) administration.
  • Exemplary modes of administration include, but are not limited to, injection, infusion, instillation, inhalation, or ingestion.
  • “Injection” includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, sub capsular, subarachnoid, intraspinal, intracerebro spinal, and intrasternal injection and infusion.
  • administration will generally be local rather than systemic.
  • the compositions are orally administered.
  • oral administration can be in the form of solutions, suspensions, tablets, pills, capsules, sustained-release formulations, oral rinses, powders and the like.
  • therapeutically-effective amount means that amount of a compound, material, or composition comprising a compound described herein which is effective for producing some desired therapeutic effect in at least a sub-population of cells, e.g., modulate or inhibit activity of MAGL in a subject at a reasonable benefit/risk ratio applicable to any medical treatment.
  • therapeutically effective amount means that amount which, when administered to a subject for treating a disease, is sufficient to affect such treatment for the disease.
  • effective doses can be calculated according to the body weight, body surface area, or organ size of the subject to be treated. Optimization of the appropriate dosages can readily be made by one skilled in the art in light of pharmacokinetic data observed in human clinical trials. Alternatively, or additionally, the dosage to be administered can be determined from studies using animal models for the particular type of condition to be treated, and/or from animal or human data obtained from agents which are known to exhibit similar pharmacological activities.
  • the final dosage regimen will be determined by the attending surgeon or physician, considering various factors which modify the action of active agent, e.g., the agent’s specific activity, the agent’s specific half-life in vivo, the severity of the condition and the responsiveness of the patient, the age, condition, body weight, sex and diet of the patient, the severity of any present infection, time of administration, the use (or not) of other concomitant therapies, and other clinical factors.
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the IC 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of use or administration utilized.
  • the effective dose can be estimated initially from cell culture assays.
  • a dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC 50 (i.e., the concentration of the therapeutic which achieves a half-maximal inhibition of symptoms) as determined in cell culture.
  • Levels in plasma can be measured, for example, by high performance liquid chromatography.
  • the effects of any particular dosage can be monitored by a suitable bioassay.
  • a treatment according to the present disclosure can be co-administered with one or more desired therapeutics or medical procedures for treating a MAGL-mediated disease or disorder.
  • Definitions [000128] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. [000129] For convenience, certain terms employed herein, in the specification, examples and appended claims are collected herein. Unless stated otherwise, or implicit from context, the following terms and phrases include the meanings provided below. Unless explicitly stated otherwise, or apparent from context, the terms and phrases below do not exclude the meaning that the term or phrase has acquired in the art to which it pertains.
  • the term “Selective MAGL Inhibitor Compound” refers to a compound that selectively inhibits MAGL with an IC 50 that is at least 10 times the IC 50 for its inhibition of fatty acid amide hydrolase (FAAH), and that has an IC 50 of 100nM or less (according to the MAGL Potency assay of Example 19 and the FAAH potency assay of Example 20).
  • the term “Reversible MAGL Inhibitor Compound” the percent inhibition after dilution to the IC 50 concentration is 50 + 15% in the assay described for “determining MAGL reversible inhibition” section of Example 21 below.
  • the term “Reversible Selective MAGL Inhibitor Compound” refers to a compound that is both a Selective MAGL Inhibitor Compound and a Reversible MAGL Inhibitor Compound, or a pharmaceutically acceptable salt thereof.
  • alkyl refers to an aliphatic hydrocarbon group which can be straight or branched having 1 to about 10 carbon atoms in the chain, and which preferably have about 1 to about 6 carbons in the chain. “Lower alkyl” refers to an alkyl group having 1 to about 4 carbon atoms. “Higher alkyl” refers to an alkyl group having about 5 to about 10 carbon atoms.
  • alkyl group can be optionally substituted with one or more alkyl group substituents which can be the same or different, where “alkyl group substituent” includes halo, amino, aryl, hydroxy, alkoxy, aryloxy, alkyloxy, alkylthio, arylthio, aralkyloxy, aralkylthio, carboxy, alkoxycarbonyl, oxo and cycloalkyl.
  • “Branched” refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl or propyl, is attached to a linear alkyl chain.
  • alkyl groups include methyl, ethyl, i-propyl, n-butyl, t-butyl, n-pentyl, heptyl, octyl, decyl, dodecyl, tridecyl, tetradecyl, pentadecyl and hexadecyl.
  • Useful alkyl groups include branched or straight chain alkyl groups of 6 to 50 carbon, and also include the lower alkyl groups of 1 to about 4 carbons and the higher alkyl groups of about 12 to about 16 carbons.
  • cycloalkyl refers to a non-aromatic mono- or multicyclic ring system of about 3 to about 12 carbon atoms.
  • Representative monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, and cyclohexyl.
  • Useful multicyclic cycloalkyl rings include adamantyl.
  • “Lower cycloalkyl” refers to an alkyl group having 3 to about 6 carbon atoms in the cycloalkyl ring, optionally substituted with halogen, alkyl, alkoxy or other substituents disclosed herein.
  • “Higher alkyl” refers to an alkyl group having about 5 to about 10 carbon atoms.
  • Aryl refers to an aromatic carbocyclic radical containing about 3 to about 10 carbon atoms.
  • the aryl group can be optionally substituted with one or more substituents, which can be the same or different, where “aryl group substituent” includes alkyl, alkenyl, alkynyl, hydroxy, alkoxy, carboxy, halo, nitro, trihalomethyl, cyano, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acyloxy, acylamino, aroylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylthio, alkylthio, and alkylene.
  • aryl groups include substituted or unsubstituted phenyl.
  • “Heterocyclyl” refers to a nonaromatic 3-8 membered monocyclic, or 8-12 membered bicyclic ring systems having 1-3 heteroatoms if monocyclic, or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, or 1-6 heteroatoms of N, O, or S if monocyclic, or bicyclic, respectively).
  • C x heterocyclyl and C x -C y heterocyclyl are typically used where X and Y indicate the number of carbon atoms in the ring system.
  • 1, 2 or 3 hydrogen atoms of each ring can be substituted by a substituent.
  • exemplary heterocyclyl groups include, but are not limited to piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolizinyl, 1,4-diazaperhydroepinyl, 1,3-dioxanyl, 1,4-dioxanyland the like.
  • Heteroaryl refers to an aromatic 3-8 membered monocyclic, or 8-12 membered fused bicyclic ring system having 1-3 heteroatoms if monocyclic, or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively.
  • Exemplary aryls and heteroaryls include, but are not limited to, phenyl, pyridinyl, pyrimidinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrazolyl, pyridazinyl, pyrazinyl, triazinyl, tetrazolyl, indolyl, benzyl, naphthyl, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, tetrahydronaphthyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benziso
  • halogen refers to an atom selected from fluorine, chlorine, bromine and iodine.
  • halogen radioisotope or “halo isotope” refers to a radionuclide of an atom selected from fluorine, chlorine, bromine and iodine.
  • haloalkyl refers to an alkyl structure with at least one substituent of fluorine, chorine, bromine or iodine, or with combinations thereof.
  • exemplary halo- substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like (e.g.
  • halosubstituted (C 1 -C 3 )alkyl includes chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl (CF 3 ), perfluoroethyl, 2,2,2-trifluoroethyl, 2,2,2-trifluoro-l,l-dichloroethyl, and the like).
  • amino means -NH 2 or -NH 3 + where one or more hydrogens are optionally substituted with alkyl, and the alkyl is optionally further substituted with one or more halogen or other substituents disclosed herein.
  • alkylamino means a nitrogen moiety having one straight or branched unsaturated aliphatic, cyclyl, or heterocyclyl radicals attached to the nitrogen, e.g., –NH(alkyl).
  • dialkylamino means a nitrogen moiety having at two straight or branched unsaturated aliphatic, cyclyl, or heterocyclyl radicals attached to the nitrogen, e.g., –N(alkyl)(alkyl).
  • alkylamino includes “alkenylamino,” “alkynylamino,” “cyclylamino,” and “heterocyclylamino.”
  • arylamino means a nitrogen moiety having at least one aryl radical attached to the nitrogen. For example, -NHaryl, and —N(aryl) 2 .
  • heteroarylamino means a nitrogen moiety having at least one heteroaryl radical attached to the nitrogen. For example —NHheteroaryl, and —N(heteroaryl) 2 .
  • two substituents together with the nitrogen can also form a ring.
  • the compounds described herein containing amino moieties can include protected derivatives thereof.
  • Suitable protecting groups for amino moieties include acetyl, tertbutoxycarbonyl, benzyloxycarbonyl, and the like.
  • Exemplary alkylamino includes, but is not limited to, NH(C 1 -C 10 alkyl), such as —NHCH 3 , —NHCH 2 CH 3 , —NHCH 2 CH 2 CH 3 , and — NHCH(CH 3 ) 2 .
  • Exemplary dialkylamino includes, but is not limited to, —N(C 1 -C 10 alkyl) 2 , such as N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —N(CH 2 CH 2 CH 3 ) 2 , and —N(CH(CH 3 ) 2 ) 2 .
  • aminoalkyl means an alkyl, alkenyl, and alkynyl as defined above, except where one or more substituted or unsubstituted nitrogen atoms (—N—) are positioned between carbon atoms of the alkyl, alkenyl, or alkynyl.
  • an (C 2 -C 6 ) aminoalkyl refers to a chain comprising between 2 and 6 carbons and one or more nitrogen atoms positioned between the carbon atoms.
  • hydroxy and “hydroxyl” mean the radical —OH.
  • alkoxyl or “alkoxy” as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto, and can be represented by one of -O-alkyl, -O- alkenyl, and -O-alkynyl.
  • Aroxy can be represented by –O-aryl or O-heteroaryl, wherein aryl and heteroaryl are as defined herein.
  • alkoxy and aroxy groups can be substituted as described above for alkyl.
  • exemplary alkoxy groups include, but are not limited to O-methyl, O-ethyl, O-n- propyl, O-isopropyl, O-n-butyl, O-isobutyl, O-sec-butyl, O-tert-butyl, O-pentyl, O- hexyl, O- cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl and the like.
  • carbonyl means the radical —C(O)—.
  • the carbonyl radical can be further substituted with a variety of substituents to form different carbonyl groups including acids, acid halides, amides, esters, ketones, and the like.
  • carboxy means the radical —C(O)O—.
  • compounds described herein containing carboxy moieties can include protected derivatives thereof, i.e., where the oxygen is substituted with a protecting group. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like.
  • a carboxy group includes –COOH, i.e., carboxyl group.
  • cyano means the radical —CN.
  • heteroatom refers to an atom that is not a carbon atom. Particular examples of heteroatoms include, but are not limited to nitrogen, oxygen, sulfur and halogens.
  • acyl refers to an alkyl-CO— group, wherein alkyl is as previously described.
  • exemplary acyl groups comprise alkyl of 1 to about 30 carbon atoms.
  • Exemplary acyl groups also include acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.
  • Alkoxycarbonyl refers to an alkyl-O—CO— group.
  • Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and t-butyloxycarbonyl.
  • Carbamoyl refers to an H 2 N—CO— group.
  • Alkylcarbamoyl refers to a R'RN—CO— group, wherein one of R and R' is hydrogen and the other of R and R' is alkyl as previously described.
  • Dialkylcarbamoyl refers to R'RN—CO— group, wherein each of R and R' is independently alkyl as previously described.
  • optionally substituted means that the specified group or moiety is unsubstituted or is substituted with one or more (typically 1, 2, 3, 4, 5 or 6 substituents) independently selected from the group of substituents listed below in the definition for “substituents” or otherwise specified.
  • substituted groups refers to a group “substituted” on a substituted group at any atom of the substituted group.
  • Suitable substituents include, without limitation, halogen, hydroxy, caboxy, oxo, nitro, haloalkyl, alkyl, alkenyl, alkynyl, alkaryl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbanoyl, arylcarbanoyl, aminoalkyl, alkoxycarbonyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano or ureido.
  • any alkyl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted with 1, 2, 3, 4 or 5 groups selected from OH, CN, SH, SO 2 NH 2 , SO 2 (C 1 - C 4 )alkyl, SO 2 NH(C 1 -C 4 )alkyl, halogen, carbonyl, thiol, cyano, NH 2 , NH(C 1 -C 4 )alkyl, N[(C 1 - C 4 )alkyl] 2 , C(O)NH 2 , COOH, COOMe, acetyl, (C 1 -C 8 )alkyl, O(C 1 -C 8 )alkyl, O(C 1 -C 8 )haloalkyl, (C 2 -C 8 )alken
  • an optionally substituted group is substituted with 1 substituent. In some other embodiments, an optionally substituted group is substituted with 2 independently selected substituents, which can be same or different. In some other embodiments, an optionally substituted group is substituted with 3 independently selected substituents, which can be same, different or any combination of same and different. In still some other embodiments, an optionally substituted group is substituted with 4 independently selected substituents, which can be same, different or any combination of same and different. In yet some other embodiments, an optionally substituted group is substituted with 5 independently selected substituents, which can be same, different or any combination of same and different.
  • Compound # As used herein, the compound designation terms “Compound # ”, “PSY-#” and “PSY-05-#” (where # indicates any number having one or more digits) are synonymous with each other, unless otherwise indicated (e.g., “Compound 1” refers to a compound alternatively designated as “PSY-05-0001” or “PSY-1”).
  • Compound 74 As used herein, Compound (PSY-05-00074) (alternatively designated as Compound 74) is: .
  • Compound (PSY-05-00074) is referred to by name as (2-fluoro-5-hydroxyphenyl)(6-(3-methyl- 1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone, or (2-fluoro-5- hydroxyphenyl) ⁇ 6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2-spiro[3.3]heptyl ⁇ methanone. Either name may be used interchangeably herein to refer to Compound (PSY-05-00074). [000163] Additional Embodiments. [000164] In some embodiments, the following methods are provided herein: A-1. A method comprising the administration of a Reversible and Selective MAGL Inhibitor Compound of Formula (I) or a pharmaceutically acceptable salt thereof,
  • each Ra is independently Cl, F, CN , cyano, methyl, or -OR 6 ;
  • R 6 is hydrogen, (C 1 -C 4 )alkyl optionally substituted with one or more F or cyclopropyl;
  • W is A, -C(O)-, -C(O)-A, -C(O)N(R 10 )-;
  • R 10 is hydrogen or methyl;
  • A is a 5-member heteroaryl ring optionally substituted with one or more R 30 ;
  • R 30 is (C 1 -C 4 )alkyl; g. m is 1, or 2; and h.
  • each R b is independently halogen, or (C 1 -C 4 )alkyl optionally substituted with one or more F.
  • A-3 The method of embodiment A-2, wherein R 30 is methyl; and each R b is independently halogen, or methyl optionally substituted with one or more F.
  • A-4. The compound of embodiment A-3, wherein A is selected from the group consisting of a. pyrazole, imidazole, or triazole, each optionally substituted with one methyl; and b. oxadiazole.
  • A-5 The method of embodiment A-4, wherein A is pyrazole substituted with one methyl.
  • A-6 The method of any one of embodiments A-1 - A-5, wherein one Ra is -OR 6 .
  • A-8 The method of embodiment A-1, of Formula (I-A): Formula (I-A), wherein R 1 is hydrogen or halogen; R 3 is hydrogen, halogen, or lower alkyl optionally substituted with one or more halogen; R 5 is hydrogen, halogen, lower alkoxy or lower alkyl each optionally substituted with one or more halogen; and R 6 is hydrogen, lower alkyl or cycloalkyl optionally substituted with one or more halogen.
  • R 1 is hydrogen or halogen
  • R 3 is hydrogen, halogen, or lower alkyl optionally substituted with one or more halogen
  • R 5 is hydrogen, halogen, lower alkoxy or lower alkyl each optionally substituted with one or more halogen
  • R 6 is hydrogen, lower alkyl or cycloalkyl optionally substituted with one or more halogen.
  • R 30 , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 and R 39 are each independently hydrogen or lower alkyl.
  • the method of embodiment A-10, wherein R 30 , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 and R 39 are each independently hydrogen or methyl.
  • the method of embodiment A-10, wherein W is A7 and Rb is methyl.
  • A-18. A method comprising the administration of a Reversible and Selective MAGL Inhibitor Compound of Formula (III), or a pharmaceutically acceptable salt thereof,
  • A-19 The method of embodiment A-18, wherein W is a 5-member heteroaryl ring comprising at least one nitrogen heteroatom optionally substituted with one methyl, the methyl optionally substituted with one or more F.
  • a method comprising the administration of a compound selected from the group consisting of:
  • A-21 A method comprising the administration of a compound selected from the group consisting of:
  • A-22. A method comprising the administration of a compound selected from the group consisting of: and .
  • A-23. A method comprising the administration of a compound selected from the group consisting of: .
  • A-24. A method comprising the administration of a compound or a pharmaceutically acceptable salt thereof.
  • A-25. A method comprising the administration of a compound or a pharmaceutically acceptable salt thereof.
  • A-26. A method comprising the administration of a compound or a pharmaceutically acceptable salt thereof.
  • A-27. A method comprising the administration of a compound or a pharmaceutically acceptable salt thereof.
  • A-28. A method comprising the administration of a compound or a pharmaceutically acceptable salt thereof.
  • a method comprising the administration of a compound or a pharmaceutically acceptable salt thereof comprising the administration of a compound or a pharmaceutically acceptable salt thereof.
  • A-30. A method comprising the administration of a compound or a pharmaceutically acceptable salt thereof.
  • A-31. A method comprising the administration of a compound or a pharmaceutically acceptable salt thereof.
  • A-32. A method comprising the administration of a compound or a pharmaceutically acceptable salt thereof.
  • a method comprising the administration of (2-fluoro-5-hydroxyphenyl)(6-(3-methyl- 1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone or (2-ethoxy-4- fluorophenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone.
  • A-34 A method comprising the administration of a Reversible Selective MAGL Inhibitor Compound.
  • A-35 A method comprising the administration of a Reversible Selective MAGL Inhibitor Compound.
  • any one of embodiments A-1 - A-34 wherein the method comprises the administration of a Reversible Selective MAGL Inhibitor Compound to a subject in an amount effective to transiently increase the level of 2-AG in the brain of the subject.
  • A-36 The method of any one of embodiments A-1 – A-34, wherein the method comprises the administration of a Reversible Selective MAGL Inhibitor Compound to a subject in an amount effective to transiently increase the level of 2-AG in the brain of the subject within about 30 minutes after administration of the Reversible Selective MAGL Inhibitor Compound.
  • A-37 wherein the method comprises the administration of a Reversible Selective MAGL Inhibitor Compound to a subject in an amount effective to transiently increase the level of 2-AG in the brain of the subject within about 30 minutes after administration of the Reversible Selective MAGL Inhibitor Compound.
  • any one of embodiments A-1 - A-34 wherein the method comprises the oral administration of a Reversible Selective MAGL Inhibitor Compound to a subject in an amount effective to transiently increase the level of 2-AG in the brain of the subject after administration of the Reversible Selective MAGL Inhibitor Compound.
  • A-38 The method of any one of embodiments A-1 - A-34, wherein the method comprises the oral administration of a Reversible Selective MAGL Inhibitor Compound to a subject in an amount effective to transiently increase the level of 2-AG in the brain of the subject after administration of the Reversible Selective MAGL Inhibitor Compound.
  • A-39 wherein the method comprises the oral administration of a Reversible Selective MAGL Inhibitor Compound to a subject in an amount effective to transiently increase the level of 2-AG in the brain of the subject after administration of the Reversible Selective MAGL Inhibitor Compound.
  • A-40 wherein the half-life of the transient increase of the 2-AG in the brain is less than twice the half-life of the Reversible Selective MAGL Inhibitor Compound in the blood plasma of the subject.
  • A-42 The method of any one of embodiments A-40 or A-41, wherein the subject is human.
  • A-43 The method of embodiment A-42, wherein the human subject is diagnosed with epilepsy prior to the administration of the Reversible Selective MAGL Inhibitor Compound.
  • A-44 A method of treating generalized epilepsy in a human subject comprising the oral administration of a therapeutically effective amount of a Reversible Selective MAGL Inhibitor Compound to the subject in need thereof.
  • A-45 A method of treating generalized epilepsy in a human subject comprising the oral administration of a therapeutically effective amount of a Reversible Selective MAGL Inhibitor Compound to the subject in need thereof.
  • the method of embodiment A-44, wherein the Reversible Selective MAGL Inhibitor Compound is a compound administered in the method of any one of embodiments A-1 – A-32, or a pharmaceutically acceptable salt thereof.
  • A-46. A method of treating post traumatic stress disorder (PTSD) in a human subject comprising the oral administration of a therapeutically effective amount of a Reversible Selective MAGL Inhibitor Compound to the subject in need thereof.
  • PTSD post traumatic stress disorder
  • A-47 The method of embodiment A-44, wherein the Reversible Selective MAGL Inhibitor Compound is a compound administered in the method of any one of embodiments A-1 – A-32, or a pharmaceutically acceptable salt thereof.
  • the compound is selected from the group consisting of: , [000166] In some embodiments, the compound is selected from the group consisting of: . [000167] In some embodiments, the compound is selected from the group consisting of: [000168] .Other compounds include the compounds shown below that are Selective MAGL Inhibitors and Reversible MAGL Inhibitors:
  • B-1 A method of transiently increasing 2-AG in the brain of a subject, the method comprising the administration of a Reversible Selective MAGL Inhibitor Compound.
  • B-2 The method of embodiment B-1, wherein the half-life of the transient increase of 2-AG in the brain of the subject is less than twice the blood plasma half-life of the Reversible Selective MAGL Inhibitor Compound.
  • B-3 The method of any one of embodiments B-1 - B-2, wherein the Reversible Selective MAGL Inhibitor Compound is orally administered to the subject.
  • B-4 A method of transiently increasing 2-AG in the brain of a subject, the method comprising the administration of a Reversible Selective MAGL Inhibitor Compound.
  • a method of treating post-traumatic stress disorder in a human subject comprising the oral administration of a therapeutically effective amount of a Reversible Selective MAGL Inhibitor Compound to the subject in need thereof.
  • B-8 The method of any one of any one of embodiments B-1 - B-7, wherein the Reversible and Selective MAGL Inhibitor Compound of Formula (I-B) or a pharmaceutically acceptable salt thereof, Formula (I-B), wherein n is 1, 2, or 3; each Ra is independently halogen, cyano, lower alkyl optionally substituted with one or more halogen, or -OR 6 ; R 6 is hydrogen, lower alkyl or lower cycloalkyl optionally substituted with one or more halogen; W is A, C(O)-, -C(O)-A, or -C(O)N(R 10 )-; R 10 is hydrogen or lower alkyl; A is a 5-member heteroaryl ring optionally substituted with one or more R 30 ; R 30 is
  • each Ra is independently Cl, F, CN , cyano, methyl, or -OR 6 ;
  • R 6 is hydrogen, (C 1 -C 4 )alkyl optionally substituted with one or more F or cyclopropyl;
  • W is A;
  • R 10 is hydrogen or methyl;
  • e. A is a 5-member heteroaryl ring optionally substituted with one or more R 30 ;
  • R 30 is (C 1 -C 4 )alkyl; g. m is 1, or 2; and h.
  • each R b is independently halogen, or (C 1 -C 4 )alkyl optionally substituted with one or more F.
  • B-10 is independently halogen, or (C 1 -C 4 )alkyl optionally substituted with one or more F.
  • R 1 is hydrogen or halogen
  • R 3 is hydrogen, halogen, or lower alkyl optionally substituted with one or more halogen
  • R 5 is hydrogen, halogen, lower alkoxy or lower alkyl each optionally substituted with one or more halogen
  • R 6 is hydrogen, lower alkyl or cycloalkyl optionally substituted with one or more halogen.
  • R 3 is hydrogen or halogen
  • R 5 is -O-R 52
  • R 52 is lower alkyl or cycloalkyl, each optionally substituted with halogen.
  • B-17 The method of any one of embodiments B-8 - B-16, wherein W is selected from the group consisting of A1, A2, A3, A4, A5, A6 and A7, , , , ,
  • R 30 , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 and R 39 are each independently hydrogen or lower alkyl.
  • B-18. The method of embodiment B-17, wherein R 30 , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 and R 39 are each independently hydrogen or methyl.
  • B-19. The method of embodiment B-17, wherein W is A1 and R 30 is methyl.
  • the method of embodiment B-17, wherein W is A7 and Rb is methyl.
  • B-25 A method comprising the administration of a Reversible and Selective MAGL Inhibitor Compound of Formula (III), or a pharmaceutically acceptable salt thereof,
  • B-26 The method of embodiment B-25, wherein W is a 5-member heteroaryl ring comprising at least one nitrogen heteroatom and optionally substituted with one methyl.
  • B-27 A method comprising the administration of a compound selected from the group consisting of:
  • a method comprising the administration of a compound selected from the group consisting of:
  • B-29 A method comprising the administration of a compound selected from the group consisting of: and . B-30. A method comprising the administration of a compound selected from the group consisting of: . B-31. A method comprising the administration of a compound or a pharmaceutically acceptable salt thereof. B-32. A method comprising the administration of a compound or a pharmaceutically acceptable salt thereof. B-33. A method comprising the administration of a compound or a pharmaceutically acceptable salt thereof. B-34. A method comprising the administration of a compound or a pharmaceutically acceptable salt thereof. B-35. A method comprising the administration of a compound or a pharmaceutically acceptable salt thereof. B-36.
  • B-37. A method comprising the administration of a compound or a pharmaceutically acceptable salt thereof.
  • B-38. A method comprising the administration of a compound or a pharmaceutically acceptable salt thereof.
  • B-39. A method comprising the administration of a compound or a pharmaceutically acceptable salt thereof.
  • B-40. A method of transiently increasing 2-AG in the brain of a subject, comprising the administration of a compound according to the method of any one of embodiments B-24 – B-39.
  • B-41. The method of embodiment B-40, wherein the compound is orally administered to the subject.
  • a method of treating epilepsy in a human subject comprising the oral administration of a therapeutically effective amount of a compound according to the methods of any one of embodiments B-24 - B-48 to the subject in need thereof.
  • a method of treating post-traumatic stress disorder in a human subject comprising the oral administration of a therapeutically effective amount of a compound according to the methods of any one of embodiments B-24 - B-45 to the subject in need thereof.
  • a method of transiently increasing 2-AG in the brain of a subject comprising the administration of (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2- azaspiro[3.3]heptan-2-yl)methanone or a pharmaceutically acceptable salt thereof.
  • B-49. The method of any one of embodiments B-1 - B-46, wherein the half-life of the transient increase of 2-AG in the brain of the subject is less than twice the blood plasma half-life of the compound.
  • B-50 The method of any one of embodiments B-1 - B-46, wherein the half-life of the transient increase of 2-AG in the brain of the subject is less than twice the blood plasma half-life of the compound.
  • a method of treating or managing epilepsy comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (II-A), or a pharmaceutically acceptable salt thereof, to treat or manage epilepsy of the subject:
  • R 3 is hydrogen, methyl optionally substituted with one or more F, or F
  • W is a 5-member heteroaryl ring comprising at least one nitrogen heteroatom optionally substituted with one methyl optionally substituted with one or more F; or cyclopropyl
  • R 20 is methyl optionally substituted with one or more F, Cl or F
  • R 26 is hydrogen or F. . B-53.
  • a method of treating or managing epilepsy comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (III-A), or a pharmaceutically acceptable salt thereof, to treat or manage the epilepsy of the subject:
  • Formula (III-A) wherein R 52 is cyclopropyl or (C 1 -C 4 ) alkyl optionally substituted with one or more F; W is C(O)N(R 10 )- and R 10 is methyl; or W is a 5-member heteroaryl ring comprising at least one nitrogen heteroatom and optionally substituted with one methyl;
  • R 20 is (C 1 -C 4 ) alkyl; and R 26 is hydrogen or F.
  • B-54 wherein R 52 is cyclopropyl or (C 1 -C 4 ) alkyl optionally substituted with one or more F; W is C(O)N(R 10 )- and R 10 is methyl; or W is a 5-member heteroaryl ring comprising at least
  • B-55. A method of treating epilepsy to a subject in need thereof, comprising the step of administering a therapeutically effective amount of a compound according to a method of any one of embodiments B-1 - B-54.
  • B-56. A method of treating epilepsy in a subject, comprising the administration to the subject in need thereof: the compound (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5- yl)-2-azaspiro[3.3]heptan-2-yl)methanone or a pharmaceutically acceptable salt thereof.
  • a method of treating PTSD in a subject comprising the administration to the subject in need thereof: the compound (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5- yl)-2-azaspiro[3.3]heptan-2-yl)methanone or a pharmaceutically acceptable salt thereof.
  • B-58 The method of any one of embodiments B-8 - B-10, B-13 - B-20, B-22 - B-26, B-40 - B- 46 and B-52 - B-53 wherein W in the compound is selected from the group consisting of: B-59.
  • the Reversible Selective MAGL Inhibitor Compound is a compound of Formula (I-A) or a pharmaceutically acceptable salt thereof: ormua ( - ), wherein A 1 is an aryl or heteroaryl optionally substituted with one or more Ra; each Ra is independently halogen, cyano, lower alkyl optionally substituted with one or more halogen, cycloalkyl, aminoalkyl, carboxy, carboxamide, or -OR 6 ; R 6 is hydrogen, lower alkyl or lower cycloalkyl optionally substituted with one or more halogen; V is selected from each p is independently 0, 1, 2, 3 or 4; each Rv is independently hydrogen, halogen, or alkyl optionally substituted with one or more halogen; W is -A 2 -, -C(O)-, C(O)-A 2 -, -C(O)N(R 10 )- and -C(O)N(R 10 )
  • R 1 is hydrogen or halogen
  • R 3 is hydrogen, halogen, or lower alkyl optionally substituted with one or more halogen
  • R 5 is hydrogen, halogen, lower alkoxy or lower alkyl each optionally substituted with one or more halogen
  • R 6 is hydrogen, lower alkyl or cycloalkyl optionally substituted with one or more halogen
  • W is A, -C(O)-, or -C(O)N(R 10 )-
  • A is aryl or heteroaryl each optionally substituted with one or more R 30 ; each R 30 is independently lower alkyl optionally substituted with one or more halogen
  • R 10 is hydrogen or lower alkyl
  • m is 1, 2, 3, 4 or 5.
  • R 3 is hydrogen or halogen
  • R 5 is -O-R 52
  • R 52 is lower alkyl or cycloalkyl, each optionally substituted with halogen
  • W is A, -C(O)-, or -C(O)N(R 10 )-
  • A is aryl or heteroaryl each optionally substituted with one or more R 30
  • each R 30 is independently lower alkyl optionally substituted with one or more halogen
  • R 10 is hydrogen or lower alkyl
  • m is 1, 2, 3, 4 or 5.
  • R 20 is lower alkyl; n is 1, 2, or 3; each Ra is independently halogen, cyano, lower alkyl optionally substituted with one or more halogen, or -OR 6 ; W is as defined with respect to Formula (I-B); and R 6 is hydrogen, lower alkyl or lower cycloalkyl optionally substituted with one or more halogen.
  • R 20 is lower alkyl; n is 1, 2, or 3; each Ra is independently halogen, cyano, lower alkyl optionally substituted with one or more halogen, or -OR 6 ; W is as defined with respect to Formula (I-B); and R 6 is hydrogen, lower alkyl or lower cycloalkyl optionally substituted with one or more halogen.
  • the Reversible Selective MAGL Inhibitor Compound is a compound of Formula (II) or a pharmaceutically acceptable salt thereof: Formula (II), wherein R 1 is halogen or cyano; R 3 is hydrogen or halogen; W is A, -C(O)-, or -C(O)N(R 10 )-; R 10 is hydrogen or lower alkyl; A is a 5-member heteroaryl ring optionally substituted with one or more R 30 ; and R 20 and R 30 are each independently lower alkyl.
  • Formula (II) wherein R 1 is halogen or cyano; R 3 is hydrogen or halogen; W is A, -C(O)-, or -C(O)N(R 10 )-; R 10 is hydrogen or lower alkyl; A is a 5-member heteroaryl ring optionally substituted with one or more R 30 ; and R 20 and R 30 are each independently lower alkyl.
  • R 3 is halogen
  • R 62 is lower alkyl or cycloalkyl, each optionally substituted with halogen
  • W is a 5-member heteroaryl ring optionally substituted with one or more R 30
  • R 30 is lower alkyl
  • R 20 is lower alkyl.
  • the Reversible Selective MAGL Inhibitor Compound is a compound of Formula (III-A) or a pharmaceutically acceptable salt thereof: ormu a ( - ) wherein R 52 is cyclopropyl or (C 1 -C 4 ) alkyl optionally substituted with one or more F; W is C(O)N(R 10 )- and R 10 is methyl; or W is a 5-member heteroaryl ring comprising at least one nitrogen heteroatom and optionally substituted with one methyl; R 20 is (C 1 -C 4 ) alkyl; and R 26 is hydrogen or F.
  • R 52 is cyclopropyl or (C 1 -C 4 ) alkyl optionally substituted with one or more F
  • W is C(O)N(R 10 )- and R 10 is methyl
  • W is a 5-member heteroaryl ring comprising at least one nitrogen heteroatom and optionally substituted with one methyl
  • R 20 is (C 1 -C 4 ) alkyl
  • any one of embodiments B-67 - B-75, wherein W in the compound is selected from the group consisting of: , , B-77.
  • the method of embodiment B-76, wherein W is B-78.
  • the method of embodiment B-76, wherein W is B-79.
  • the method of embodiment B-76, wherein W is B-80.
  • the method of embodiment B-76, wherein W is B-81.
  • the method of embodiment B-76, wherein W is B-82.
  • the method of embodiment B-76, wherein W is . B-83.
  • the method of embodiment B-76, wherein W is B-84.
  • the method of embodiment B-66, wherein the compound is a compound selected from the group consisting of: , , , , ,
  • B-102 The method of embodiment B-66, wherein the compound is 2-fluoro-5- hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptan-2- yl)methanone.
  • B-103 The method of any one of embodiments B-67 - B-102, wherein the disorder is epilepsy. [000171] In some embodiments, the following methods are provided herein: C-1.
  • a method of treating a neurological disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of: (2,4-difluoro-5-hydroxyphenyl) ⁇ 6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2- spiro[3.3]heptyl ⁇ methanone (Compound 126); 4-hydroxy-2-( ⁇ 6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2- spiro[3.3]heptyl ⁇ carbonyl)benzonitrile (Compound 128); [4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl] ⁇ 6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2- spiro[3.3]heptyl ⁇ methanone (Compound 178); (2-fluoro-5-hydroxyphenyl) ⁇ 6-[3
  • C-2 The method of embodiment C-1, wherein the neurological disorder is epilepsy.
  • C-3 The method of embodiment C-1, wherein the neurological disorder is treating symptoms of epilepsy.
  • C-4 The method of any one of embodiments C-1 - C-3, wherein the compound is (2,4- difluoro-5-hydroxyphenyl) ⁇ 6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2- spiro[3.3]heptyl ⁇ methanone (Compound 126), or a pharmaceutically acceptable salt thereof.
  • Compound 126 Compound 126
  • a method of reversibly inhibiting MAGL in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of: (2,4-difluoro-5-hydroxyphenyl) ⁇ 6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2- spiro[3.3]heptyl ⁇ methanone (Compound 126); 4-hydroxy-2-( ⁇ 6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2- spiro[3.3]heptyl ⁇ carbonyl)benzonitrile (Compound 128); [4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl] ⁇ 6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2- spiro[3.3]heptyl ⁇ methanone (Compound 178); (2-fluoro-5-hydroxyphenyl)
  • a method of treating epilepsy in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of: (2,4-difluoro-5-hydroxyphenyl) ⁇ 6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2- spiro[3.3]heptyl ⁇ methanone (Compound 126), or a pharmaceutically acceptable salt thereof; 4-hydroxy-2-( ⁇ 6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2- spiro[3.3]heptyl ⁇ carbonyl)benzonitrile (Compound 128), or a pharmaceutically acceptable salt thereof; [4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl] ⁇ 6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2- spiro[3.3]heptyl ⁇ methanone (Compound 126),
  • D-2 The method of embodiment D-1, wherein the compound is (2,4-difluoro-5- hydroxyphenyl) ⁇ 6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2-spiro[3.3]heptyl ⁇ methanone (Compound 126), or a pharmaceutically acceptable salt thereof.
  • D-3 The method of embodiment D-1, wherein the compound is 4-hydroxy-2-( ⁇ 6-[3- methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2-spiro[3.3]heptyl ⁇ carbonyl)benzonitrile (Compound 128), or a pharmaceutically acceptable salt thereof.
  • D-4 The method of embodiment D-1, wherein the compound is (2,4-difluoro-5- hydroxyphenyl) ⁇ 6-[3-methyl-1-(o-tolyl)-5-pyrazolyl]-2-aza-2-spiro[3.3]heptyl ⁇ carbonyl)benzonitrile
  • D-11 The method of embodiment D-1, wherein the compound is ⁇ 6-[3-(2-chloro-5- fluorophenyl)-4-methyl-1-pyrazolyl]-2-aza-2-spiro[3.3]heptyl ⁇ (2-fluoro-5- hydroxyphenyl)methanone (Compound 520), or a pharmaceutically acceptable salt thereof.
  • D-12 The method of embodiment D-1, wherein the compound is ⁇ 6-[5-(2,5- difluorophenyl)-4-methyl-1-pyrazolyl]-2-aza-2-spiro[3.3]heptyl ⁇ (2-fluoro-5- hydroxyphenyl)methanone (Compound 476), or a pharmaceutically acceptable salt thereof.
  • D-13 The method of embodiment D-1, wherein the compound is ⁇ 6-[3-(2-chloro-5- fluorophenyl)-4-methyl-1-pyrazolyl]-2-aza-2-spiro[3.3]heptyl ⁇ (2-fluoro-5-
  • any one of embodiments D-1 – D-12 wherein the administration of the compound transiently increases a level of 2-AG in a brain of the subject.
  • D-14 The method of any one of embodiments D-1 – D-12, wherein a half-life of the transient increase of the level of 2-AG in the brain of the subject is less than twice the half-life of the compound in a blood plasma of the subject.
  • D-15 The method of any one of embodiments D-1 – D-12, wherein the administration is oral administration; and wherein the administration of the compound transiently increases a level of 2-AG in a brain of the subject within about 30 minutes after the oral administration of the compound to the subject.
  • D-16 The method of any one of embodiments D-1 – D-12, wherein the administration of the compound transiently increases a level of 2-AG in a brain of the subject within about 30 minutes after the oral administration of the compound to the subject.
  • SAR127303 48 nM IC50 against recombinant human—rhMAGL was shown ineffective in acute seizure tests in different models (6-Hz stimulation, pentylenetetrazol—PTZ seizure threshold, and kainic acid models) (Griebel G, Pichat P, Beeske S, et al. Selective blockade of the hydrolysis of the endocannabinoid 2-arachidonoylglycerol impairs learning and memory performance while producing antinociceptive activity in rodents. Scientific Reports. 2015;5. doi:10.1038/srep07642).
  • reversible inhibitors are less likely to induce tolerance and offer many potential advantages for epilepsy treatment such as providing fine-tuned control, reducing the risk of overdosing, minimizing side effects, allowing for dynamic treatment response, facilitating a faster onset and offset of action, and enabling potential combination therapy.
  • Step-2 5-bromo-3-methyl-1-(o-tolyl)-1H-pyrazole: [000180] To a stirred solution of 3-methyl-1-(o-tolyl)-1H-pyrazol-5-ol (15g, 79.7 mmol) in toluene (300 ml) was added POBr3 (91.5g, 319.14 mmol) at rt. The reaction was stirred at 120 °C for 48h. After completion of reaction as monitored by TLC, the reaction mixture was quenched sat. NaHCO3 (750ml) and extracted with ethyl acetate (500ml*3).
  • Step-3 tert-butyl 6-hydroxy-6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptane-2- carboxylate: [000181] To a stirred solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (6.5g, 0.0306 mol) and 5-bromo-3-methyl-1-(o-tolyl)-1H-pyrazole (11.5g, 0.459 mol) in THF (130 ml) was added 2M n-BuLi in hexane (24.5 ml, 0.049 mol) at -78 °C, 2h.
  • Step-5 tert-butyl 6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptane-2- carboxylate.
  • Step-6 6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptane 2,2,2-trifluoroacetate.
  • reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (3*100 ml). The organic layer was washed with brine (3*50ml), dried over sodium sulphate and concentrated under vacuum to get crude material which was purified by combiflash using 3% MeOH in DCM as eluent. The compound was further purified by Prep-HPLC purification. The fraction was lyophilized to get PSY-05-00074 as white solid (0.45g, 26%). LCMS: 406.7 m/z [M+H]+.
  • the potency of Compound 74 for inhibiting MAGL was obtained using the following assay.
  • the monoacylglycerol lipase inhibitor screening assay kit from Cayman Chemical was used to measure the MAGL potency for the compounds in Table A and Table B below.
  • Cayman’s Monoacylglycerol Lipase Inhibitor Screening Assay provides a method for screening human MAGL inhibitors.
  • MAGL hydrolyzes 4-nitrophenylacetate resulting in a yellow product, 4- nitrophenol, with an absorbance of 405-412 nm.
  • Example 3 Synthesis of (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2- azaspiro[3.3]hept-5-en-2-yl)methanone.
  • reaction mixture was concentrated to get crude material.
  • the crude material was triturated with mixture of diethyl ether and hexane (1:1, 10 mL*3) to get pure desire compound (0.11 g, quantitative) as a white solid.
  • Step-2 (2-fluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2- azaspiro[3.3]hept-5-en-2-yl)methanone [000189] To a stirred solution of 6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]hept- 5-ene 2,2,2-trifluoroacetate (0.11 g, 0.421 mmol) in DMF (1 mL) were added 2-fluoro-5- hydroxybenzoic acid (0.054g, 0.506 mmol), TEA (0.088g, 1.26 mmol) and T3P (0.111g, 0.506 mmol) at 0 °C.
  • reaction mixture was stirred at room temperature for 2h. After completion of reaction as monitored by TLC, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3*50 mL). The organic layer was washed with brine (3*25 mL), dried over sodium sulphate and concentrated under vacuum to get crude material which was purified by combiflash using 3% MeOH in DCM as eluent to get ((2-fluoro-5-hydroxyphenyl)(6- (3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]hept-5-en-2-yl)methanone) PSY-05- 00120 (0.03 g, 27%) as white solid.
  • Step-2 Synthesis of 4-fluoro-2-isopropoxybenzoic acid carbonate (Int-3).
  • Int-3 4-fluoro-2-isopropoxybenzoic acid carbonate
  • the reaction mixture was stirred at 50 o C for next 12 hr.
  • the progress of the reaction was monitored by TLC; after completion of reaction, the reaction mixture was evaporated under vacuum.
  • Step-3 Synthesis of (4-fluoro-2-isopropoxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2- azaspiro[3.3]heptan-2-yl)methanone (Compound-00177).
  • reaction mixture was stirred at room temperature for 12h. After completion of reaction as monitored by TLC, the reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (3*20 ml). The organic layer was washed with brine (10ml), dried over sodium sulphate and concentrated under vacuum to get crude material which was purified by combiflash using 50% Ethyl acetate in hexane as eluent to get PSY-05-00177 as white solid (0.040. (Yield: 16%); LCMS: 448.5 m/z [M+H] + .
  • Example 5 Synthesis of (2,4-difluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5- yl)-2-azaspiro[3.3]heptan-2-yl)methanone.
  • Step-2 5-(benzyloxy)-2,4-difluorobenzoic acid (Int-3).
  • benzyl 5-(benzyloxy)-2,4-difluorobenzoate (Int-2) (0.50 gm, 1.44 mmol,1.0 eq.) in Tetrahydrofuran (5.0 mL), Methanol (5.0 mL), Water (5.0 mL) was added Sodium Hydroxide [NaOH] (0.11 gm, 2.89 mmol, 2.0 eq.) at 0°C.
  • the reaction mixture was stirred at Room temperature for next 12 hr.
  • the progress of the reaction was monitored by TLC; after completion of reaction, the reaction mixture was evaporated under vacuum.
  • Step-3 Synthesis of (5-(benzyloxy)-2,4-difluorophenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5- yl)-2-azaspiro[3.3]heptan-2-yl)methanone (Int-4).
  • reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 X 20 mL), washed with brine. The organic layer was dried over sodium sulphate and concentrated under vacuum to get crude material; which was purified by combi-flash by using 80% Ethyl acetate in Hexane as mobile phase to give desired product (5- (benzyloxy)-2,4-difluorophenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2- azaspiro[3.3]heptan-2-yl)methanone (Int-4) 0.25 gm (Yield: 52.08%); LCMS: 514.05m/z [M + ].
  • Step-4 Synthesis of (2,4-difluoro-5-hydroxyphenyl)(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2- azaspiro[3.3]heptan-2-yl) methanone (Compound-00126).
  • Example 6 Synthesis of 4-hydroxy-2-(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2- azaspiro[3.3]heptane-2-carbonyl)benzonitrile
  • Step-1 Methyl 2-bromo-5-hydroxybenzoate (2): [000190] To stirred solution of 2-bromo-5-hydroxybenzoic acid (0.5g, 2.325 mmol), in MeOH, Con. H 2 SO 4 (2 mL) was added dropwise. The reaction mixture was heated to 90 o C and stirred at same temperature for 2h.
  • Step-2 Methyl 2-cyano-5-hydroxybenzoate (3): [000191] To stirred solution of methyl 2-bromo-5-hydroxybenzoate (0.3 g, 1.31 mmol) in DMA, was added CuCN (0.174g, 1.89 mmol) and stirred at 135 °C for 2h. The reaction was quenched by the addition of cold water (50 mL) and extracted with ethyl acetate (3x25 mL). The organic layer was concentrated and purified by combiflash using 30 % ethylacetate in hexane to give methyl 2-cyano-5-hydroxybenzoate (140 mg, 61%) as a white solid.
  • Step-3 (4-hydroxy-2-(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptane-2- carbonyl)benzonitrile) (Compound-00128): [000192] To stirred solution of 6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2- azaspiro[3.3]heptane 2,2,2-trifluoroacetate (0.120 g, 0.449 mmol) and methyl 2-cyano-5- hydroxybenzoate (0.0795 g, 0.449 mmol) in THF at -78 o C, was added LiHMDS (1.35 mL, 1.347 mmol; 1 M solution in THF) for 15 min then it stirred at rt for 3h.
  • reaction mass was quenched by the addition of water (50 mL) and extracted by ethyl acetate (3x30 mL).
  • the organic layer was concentrated under reduced pressure and purified by combiflash using 5 % MeOH in DCM to give (4-hydroxy-2-(6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro[3.3]heptane-2- carbonyl)benzonitrile) (60 mg 21%) as a white solid.
  • Example 7 Synthesis of 4-fluoro-3-((6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro [3.3] heptan-2-yl)methyl)phenol.
  • Step-1 Synthesis of 4-fluoro-3-(hydroxymethyl) phenyl isobutyl carbonate (Int-2)
  • IBCF isobutyl chloroformate
  • reaction mixture was filtered through Celite pad was washed with THF, filtered obtained was taken in single neck flask under N2 atm. to that sodium borohydride (0.219 gm, 5.769 mmol, 0.9 eq.) was added at 0°C and allowed to stirred reaction mixture for next 12 hr.
  • sodium borohydride 0.219 gm, 5.769 mmol, 0.9 eq.
  • the progress of the reaction was monitored on TLC, after completion of reaction, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 X 50 mL), washed with sat. NaHCO3 and brine.
  • Step-2 Synthesis of 4-fluoro-3-formylphenyl isobutyl carbonate (Int-3) [000194] To a stir solution of 4-fluoro-3-(hydroxymethyl)phenyl isobutyl carbonate (Int-2) (0.35 gm, 1.446 mmol, 1 eq.) in DCM (10 mL) were added Pyridinium Chlorochromate [PCC] (0.46 gm, 2.16 mmol, 1.5 eq.) at 0°C. The resulting reaction mixture was stirred at room temperature for next 3 hr.
  • PCC Pyridinium Chlorochromate
  • Step-3 Synthesis of 4-fluoro-3-((6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro [3.3] heptan-2-yl) methyl) phenol (Compund-00150) [000195]
  • 6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro [3.3] heptane (Int-9) (0.20 gm, 0.749 mmol, 1 eq.) in Methanol (10 mL) were added 4-fluoro-3- formylphenyl isobutyl carbonate (Int-3) ( 0.179 gm, 0.749 mmol, 1 eq.) followed by zinc(II) chloride (0.050 gm, 0.374 mmol, 0.5 eq.) was added to that reaction mixture at Room temperature and stirred the reaction mixture at 50oC for next 12 hr
  • Example 8 Synthesis of 2-(2-Fluoro-5-hydroxybenzoyl)-N-Methyl-N-(o-tolyl)-2-azaspiro [3.3] heptane-6-carboxamide [Compound 185] and 2-(2-Ethoxy-4-fluorobenzoyl)-N-Methyl-N-(o- tolyl)-2-azaspiro [3.3] heptane-6-carboxamide [Compound 187] Reaction Scheme: Step-1: - Synthesis of Tert-butyl 6-(methyl(o-tolyl) carbamoyl)-2-azaspiro [3.3] heptane-2- carboxylate (Int-D) [000196] Tert-buty l 6-(o-tolylcarbamoyl)-2-azaspiro [3.3] heptane-2-carboxylate 0.5 g (1.5151 mmol, 1 eq.) dissolved in Dimethylformamide 5 mL.
  • Step-2 - Synthesis of N-Methyl-N-(o-tolyl)-2-azaspiro [3.3] heptane-6-carboxamide (Int-E) [000197] Tert-butyl 6-(methyl(o-tolyl) carbamoyl)-2-azaspiro [3.3] heptane-2-carboxylate 0.5 g was taken in Dichloromethane 50mL, cooled it to 0oC, Trifluoroacetic acid 0.8 mL was added, stirred reaction mixture at room temperature for 5 hr. Reaction was monitored on TLC.
  • Step-3 - Synthesis of 2-(2-Fluoro-5-hydroxybenzoyl)-N-Methyl-N-(o-tolyl)-2-azaspiro [3.3] heptane-6-carboxamide (Compound-00187) [000198]
  • 2-Fluoro-4-hydroxy benzoic acid 0.1 g (0.676 mmol, 1.1 eq.) in Dimethylformamide 2 mL.
  • TFA salt of N-Methyl-N-(o-tolyl)-2-azaspiro [3.3] heptane-6- carboxamide 0.15 g (0.6147 mmol, 1 eq.) added and stir for 10min.
  • Desired product obtained as 2-(2-Fluoro-5- hydroxybenzoyl)-N-Methyl-N-(o-tolyl)-2-azaspiro [3.3] heptane-6-carboxamide 0.05 g (Solid).
  • Step-4 - Synthesis of 2-(2-Ethoxy-4-fluorobenzoyl)-N-Methyl-N-(o-tolyl)-2-azaspiro [3.3] heptane-6-carboxamide (Compound-00187) [000199] To a solution of 2-Ethoxy-4-fluorobenzoic acid 0.15 g (0.676 mmol, 1.1 eq.) in Dimethyl formamide 2 mL.
  • Example 9 Synthesis of (2-fluoro-5-hydroxyphenyl)(6-(1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro [3.3] heptan-2-yl) methanone [Compound 367] Synthetic scheme: Step-1: Synthesis of tert-butyl 6-(methoxy (methyl) carbamoyl) -2-azaspiro [3.3] heptane-2- carboxylate (Int-2).
  • Step-2 Synthesis of tert-butyl 6-acetyl-2-azaspiro [3.3] heptane-2-carboxylate (Int-3) [000201] To a stirred solution of tert-butyl 6-(methoxy (methyl) carbamoyl)-2-azaspiro [3.3] heptane-2-carboxylate (Int-2) (1.7gm, 5.98 mmol, 1.0 eq.) in THF was added Methyl magnesium bromide (3M in THF) (5.98 mL, 17.95 mmol, 3.0 eq.) under inert atmosphere at -30°C. The reaction mixture was stirred at Room temperature for next 12 hr.
  • Methyl magnesium bromide 3M in THF
  • reaction mixture was cooled to 0oC and quenched with saturated ammonium chloride solution (10mL) further diluted with water (30mL) and extracted with ethyl acetate (3 X 30 mL), washed with brine.
  • Step-3 Synthesis of tert-butyl (E)-6-(3-(dimethylamino) acryloyl)-2-azaspiro [3.3] heptane-2- carboxylate (Int-4).
  • tert-butyl 6-acetyl-2-azaspiro[3.3]heptane-2-carboxylate (Int- 3) 0.050 gm, 0.209 mmol, 1.0 eq.
  • Toluene (1 mL) was added DMF-DMA (0.074 gm, 0.627 mmol, 3.0 eq.) and allowed to stirred the reaction at 100oC for 12 hr; the progress of the reaction of the was monitored by TLC.
  • Step-6 Synthesis of (5-(benzyloxy)-2-fluorophenyl) (6-(1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro [3.3] heptan-2-yl) methanone (Int-7) [000205] To a stirred solution of 5-(benzyloxy)-2-fluorobenzoic acid 6-(1-(o-tolyl)-1H-pyrazol- 5-yl)-2-azaspiro [3.3] heptane (Int-6A) (0.25 gm, 1.016 mmol, 1.0 eq.) in N
  • Step-1 Synthesis of [(2-chloro-5-hydroxyphenyl) (6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2- azaspiro [3.3] heptan-2-yl) methanone] [Compound-00140] [000207] To a stirred solution of 6-(3-methyl-1-(o-tolyl)-1H-pyrazol-5-yl)-2-azaspiro [3.3] hept-5-ene 2,2,2-trifluoroacetate (0.100 gm, 0.2624 mmol) in DMF (5.0 mL) were added 2- chloro-5-hydroxybenzoic acid (0.054 gm, 0.314 mmol), Triethylamine (0.106 gm, 1.049 mmol) and Propanephosphonic acid anhydride [T3P, 50 wt.
  • Step-1 Synthesis of tert-butyl 6-((2-isopropylphenyl)carbamoyl)-2-azaspiro[3.3]heptane-2- carboxylate (Int-2).
  • 2-(tert-butoxycarbonyl)-2-azaspiro [3.3] heptane-6- carboxylic acid (0.30 gm, 1.24 mmol, 1 eq.) in N,N-Dimethyl formamide (5 mL) were added HATU (0.70 gm, 1.86 mmol, 1.5 eq.) DIPEA (0.802 gm, 6.22 mmol, 5.0 eq.) followed by addition of 2-isopropylaniline (Int-1A) (0.21 gm, 1.24 mmol, 1.0 eq.) at 0°C and allowed to stirred the reaction at room temperature for 12 hr; the progress of the reaction of was monitored by TLC.
  • Int-1A 2-isopropylaniline
  • reaction mixture was diluted with Ice cold water (10 mL) and extracted with Ethyl acetate (2 x 30mL). The combined organic layer was washed with brine solution, dried over sodium sulfate and concentrated to obtain crude product, which was purified by combiflash using 30% Ethyl acetate in Hexane as eluent to afford tert-butyl 6-((2- isopropylphenyl)(methyl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (Int-3) 0.31 gm, (Yield-75.60%).
  • Step-3 Synthesis of N-(2-isopropylphenyl)-N-methyl-2-azaspiro [3.3] heptane-6-carboxamide (Int-4).
  • Int-4 N-(2-isopropylphenyl)-N-methyl-2-azaspiro [3.3] heptane-6-carboxamide
  • tert-butyl 6-((2-isopropylphenyl)(methyl)carbamoyl)-2-azaspiro [3.3] heptane-2-carboxylate (Int-3) (0.50 gm, 1.33 mmol, 1.0 eq.) in Dichloromethane (10 mL) was added Trifluoroacetic acid (1.0 mL) at 0oC and allowed to stirred the reaction at Room temperature for 3 hr; the progress of the reaction of the was monitored by TLC.
  • Example 12 Synthesis of 2-(2-ethoxy-4-fluorobenzoyl)-N-ethyl-N-(o-tolyl)-2-azaspiro [3.3] heptane-6-carboxamide [Compound 203] Synthetic scheme: Step-1: Synthesis of tert-butyl o-tolyl carbamate (Int-2).
  • reaction mixture was diluted with Ice cold water (10 mL) and extracted with Ethyl acetate (2 x 30mL). The combined organic layer was washed with brine solution, dried over sodium sulfate and concentrated to obtain crude product, which was purified by combiflash using 30% Ethyl acetate in Hexane as eluent to afford tert- butyl ethyl(o-tolyl)carbamate (Int-3) 0.45 gm, (Yield-80.35%).
  • Step-4 Synthesis of 2-(2-ethoxy-4-fluorobenzoyl)-N-ethyl-N-(o-tolyl)-2-azaspiro [3.3] heptane- 6-carboxamide (Compound-00203).
  • Example 13 Synthesis of N-(2-chlorophenyl)-2-(2-ethoxy-4-fluorobenzoyl)-N-methyl-2-azaspiro [3.3] heptane -6-carboxamide
  • Step- 1 Synthesis of N-(2-chlorophenyl)-2-(2-ethoxy-4-fluorobenzoyl)-2-azaspiro [3.3] heptane- 6-carboxamide (Int-6).
  • Example 14 Synthesis of (4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl) (6-(3-methyl-1-(o-tolyl) -1H- pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl) methanone.
  • Step-1 Synthesis of methyl 4-fluoro-2-(2, 2, 2-trifluoroethoxy) benzoate (Int-2).
  • reaction mixture was diluted with Ice cold water (5 mL) and extracted with Ethyl acetate (2 x 20mL). The combined organic layer was washed with brine solution, dried over sodium sulfate and concentrated to obtain crude product, which was purified by combiflash using 10% Ethyl acetate in Hexane as eluent to afford methyl 4-fluoro-2-(2,2,2-trifluoroethoxy)benzoate (Int-2) 0.10 gm, (Yield-68%). The compound was containing disubstituted product which was non separable by column chromatography was carried forward as a mixture for next step.
  • Step-2 Synthesis of 4-fluoro-2-(2,2,2-trifluoroethoxy)benzoic acid (Int-3).
  • Int-3 4-fluoro-2-(2,2,2-trifluoroethoxy)benzoic acid
  • Step-3 Synthesis of (4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl)(6-(3-methyl-1-(o-tolyl)-1H- pyrazol-5-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (Compound-00178-001).
  • reaction mixture was stirred at room temperature for 12h. After completion of reaction as monitored by TLC, the reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (3*20 ml). The organic layer was washed with brine (10ml), dried over sodium sulphate and concentrated under vacuum to get crude material which was purified by combiflash using 80% Ethyl acetate in hexane as eluent to get PSY-05- 00178 as white solid (0.050.
  • Example 15 Synthesis of (2-cyclopropoxy-4-fluorophenyl)(6-(3-(trifluoromethyl)-5-(2- (trifluoromethyl) phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (Compound 424); and (2-cyclopropoxy-4-fluorophenyl)(6-(5-(trifluoromethyl)-3-(2-(trifluoromethyl) phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (Compound 451) Synthetic scheme: Step-A: 4,4,4-trifluoro-1-(2-(trifluoromethyl)phenyl)butane-1,3-dione (Int-B).
  • Step-5 (2-cyclopropoxy-4-fluorophenyl)(6-(3-(trifluoromethyl)-5-(2-(trifluoromethyl) phenyl)- 1H-pyrazol-1-yl)-2-azaspiro [3.3] heptan-2-yl)methanone (PSY-05-00424-001) and (2-cyclopropoxy-4-fluorophenyl)(6-(5-(trifluoromethyl)-3-(2-(trifluoromethyl) phenyl)-1H- pyrazol-1-yl)-2-azaspiro [3.3] heptan-2-yl) methanone (PSY-05-00451-001).
  • Fraction-1 (2-cyclopropoxy-4-fluorophenyl)(6-(5-(trifluoromethyl)-3-(2- (trifluoromethyl) phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05- 00451-001) (0.027 g, 4.97 %).
  • LCMS m/z 553.91 [M+1] + .
  • Fraction-2 (2-cyclopropoxy-4-fluorophenyl)(6-(3-(trifluoromethyl)-5-(2- (trifluoromethyl) phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05- 00424-001) (0.050 g, 9.20 %).
  • LCMS m/z 553.91 [M+1] + .
  • Example 16 Synthesis of (2-fluoro-5-hydroxyphenyl)(6-(5-(2-fluorophenyl)-4- (trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone [Compound 472] and (2-fluoro-5-hydroxyphenyl)(6-(3-(2-fluorophenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2- azaspiro[3.3]heptan-2-yl)methanone [Compound 473].
  • Step-2 (Z)-3-(dimethylamino)-1-(2-fluorophenyl)-2-(trifluoromethyl) prop-2-en-1-one (Int- 3).
  • Step-4 Tert-butyl6-(5-(2-fluoro-phenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro [3.3] heptane-2-carboxylate (Int-5) and tert-butyl6-(3-(2-fluoro-phenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro [3.3] heptane-2-carboxylate (Int-5A) [000230] To a solution of 5-(2-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-pyrazole (Int-4) (0.900 g, 3.9121 mmol, 1.0 eq.) in N,N-Dimethylformamide (10 mL), tert-butyl 6-((methyl sulfonyl) oxy)-2-azaspiro[3.3]heptane-2-carboxy
  • reaction mixture was poured into water (20 mL), and the solution was extracted with ethyl acetate (3 ⁇ 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • Step-5 6-(5-(2-fluoro-phenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro [3.3] heptane (Int-6) and 6-(3-(2-fluoro-5phenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-azaspiro [3.3] heptane (Int- 6A).
  • Step-6 2-fluoro-5-hydroxyphenyl)(6-(5-(2-fluorophenyl)-4-(trifluoromethyl)-1H-pyrazol-1- yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00474-001) and 2-fluoro-5-hydroxyphenyl)(6-(3-(2-fluorophenyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl)-2- azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00475-001).
  • Fraction-1 (2-fluoro-5-hydroxyphenyl)(6-(3-(2-fluorophenyl)-4-(trifluoromethyl)- 1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methanone (PSY-05-00473-001) (0.012 g 1.68 %).
  • LCMS m/z 464.01 [M+H] + .
  • Example 17 Synthesis of (6-(5-(2,5-Difluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro [3.3] heptan-2-yl) (2-fluoro-5-hydroxyphenyl) methanone [Compound 476] and (6-(3-(2,5-Difluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro [3.3] heptan-2-yl) (2-fluoro-5- hydroxyphenyl) methanone [Compound 477] Synthetic scheme: Step-1: Synthesis of (Z)-1-(2, 5-Difluorophenyl)-3-(dimethyl amino)-2-methylprop-2-en-1- one (Int-2).
  • Step-2 Synthesis of 5-(2,5-Difluorophenyl)-4-methyl-1H-pyrazole (Int-3) [000236] To a stirred solution of (Z)-1-(2,5-Difluorophenyl)-3-(dimethylamino)-2- methylprop-2-en-1-one (1.1 g, 4.88 mmol, 1.0 eq.) in Isopropyl alcohol (20 mL) was added hydrazine hydrate (0.36mL, 7.33 mmol, 1.5 eq.) the reaction mass was heated at 80 °C for 16h. After completion of reaction as monitored by TLC and LCMS, the reaction mixture was concentrated to get residue.
  • Step-3 Synthesis of Tert-butyl 6-(5-(pyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2- azaspiro[3.3]heptane-2-carboxylate and Tert-butyl 6-(3-(pyridin-3-yl)-5-(trifluoromethyl)- 1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (mix of Int-4 and Int-4A) [00 0237] To a well stirred reaction mixture of 3-(3-(Trifluoromethyl)-1H-pyrazol-5-yl) pyridine (0.800 g, 4.12 mmol, 1.0 eq.), CS 2 CO 3 (2.01 g, 6.18 mmol, 1.5 eq.) in N,N-di methyl formamide (10 mL) was added Tert-butyl 6-((methyl sulfonyl)
  • reaction was heated at 100 °C for 12 h. After completion of reaction as monitored by TLC, the reaction mixture was poured in water (100 mL) and extracted with ethyl acetate (50 mL*3). The organic layer was washed with brine (100 mL), dried over Sodium sulphate and concentrated under reduce pressure to get residue. The residue was purified by combi flash using 30-50% ethyl acetate in hexane as eluent to get to mixture of Int-4 and Int-4A (1.0 g, 62.5%).
  • Step-4 Synthesis of 6-(5-(2,5-difluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2- azaspiro[3.3]heptane TFA salt (Int-5) and 6-(3-(2,5-difluorophenyl)-4-methyl-1H-pyrazol- 1-yl)-2-azaspiro[3.3]heptane TFA salt (Int-5A).
  • TFA 2.0 mL
  • Step-5 Synthesis of (6-(5-(2,5-Difluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro [3.3] heptan-2-yl) (2-fluoro-5-hydroxyphenyl) methanone and (6-(3-(2,5-Difluorophenyl)-4- methyl-1H-pyrazol-1-yl)-2-azaspiro [3.3] heptan-2-yl) (2-fluoro-5-hydroxyphenyl) methanone (PSY-05-00476-001 and PSY-05-00477-001).
  • reaction mixture was poured in water (100 mL) and extracted with ethyl acetate (50 mL*3). The organic layer was washed with saturated solution of sodium carbonate (50 mL) and brine (100 mL), dried over sodium sulphate (Na 2 SO 4 ) and concentrated under reduce pressure to get residue. The residue was purified by combi flash using 40-50% ethyl acetate in hexane as eluent. The crude was submitted to prep-HPLC for purification.
  • Example 18 Synthesis of (6-(5-(2-chloro-5-fluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro [3.3] heptan-2-yl) (2-fluoro-5-hydroxyphenyl) methanone [Compound 519], and (6-(3-(2-chloro- 5-fluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro [3.3] heptan-2-yl)(2-fluoro-5- hydroxyphenyl)methanone [Compound 520] Synthetic scheme: Step-A: 2-chloro-5-fluoro-N-methoxy-N-methylbenzamide (Int-B).
  • Step-1 (E)-1-(2-chloro-5-fluorophenyl)-3-(dimethylamino)-2-methylprop-2-en-1-one (Int- 2).
  • Step-3 (5-(benzyloxy)-2-fluorophenyl)(6-(5-(2-chloro-5-fluorophenyl)-4-methyl- 1H-pyrazol-1-yl)-2-azaspiro [3.3] heptan-2-yl) methanone (Int- 4) and (5-(benzyloxy)-2-fluorophenyl)(6-(3-(2-chloro-5-fluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2- azaspiro [3.3] heptan-2-yl) methanone (Int- 4A).
  • reaction mixture was poured in water (30 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with brine (30 mL), dried over Sodium sulfate and concentrated under reduce pressure to get residue.
  • Step-4 (6-(5-(2-chloro-5-fluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro [3.3] heptan-2-yl) (2-fluoro-5-hydroxyphenyl) methanone (PSY-05-00519-001) and (6-(3-(2-chloro-5-fluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro [3.3] heptan-2-yl)(2- fluoro-5-hydroxyphenyl) methanone (PSY-05-00520-001).
  • Fraction-1 (6-(5-(2-chloro-5-fluorophenyl)-4-methyl-1H-pyrazol-1-yl)-2-azaspiro [3.3] heptan-2-yl) (2-fluoro-5-hydroxyphenyl) methanone (PSY-05-00519-001) (0.062 g, 15.01 %).
  • LCMS m/z 444.40 [M+1] + .
  • Example 19 Measuring MAGL Inhibition Potency (IC 50 )
  • the potency of certain compounds for inhibiting MAGL were obtained using the following assays.
  • the monoacylglycerol lipase inhibitor screening assay kit from Cayman Chemical was used to measure the MAGL potency for the compounds in Table 3 and Table 4.
  • Cayman’s Monoacylglycerol Lipase Inhibitor Screening Assay provides a method for screening human MAGL inhibitors.
  • MAGL hydrolyzes 4-nitrophenylacetate resulting in a yellow product, 4-nitrophenol, with an absorbance of 405-412 nm.
  • MAGL Inhibition was measured by the following assay.
  • Monoacylglycerol Lipase (MAGL) inhibition was measured using recombinant MAGL enzyme (aa 2-303 RBC, internal preparation) and the substrate 4-Nitrophenyl acetate (4NPA) (Sigma-Aldrich, N8130). Hydrolysis of the substrate in the presence of the enzyme was measured by absorbance at 405 nm.10 ⁇ L of assay buffer (10 mM Tris pH 7.5, 1 mM EDTA, 0.9% DMSO) was added to a black 384-well non-binding plate with clear bottom (Greiner, 781906) for each reaction. Compounds were dispensed using an acoustic liquid handler (Echo, Beckman) at 45 nL (0.1% DMSO).
  • Test compounds and control for MAGL inhibitor JZL-184 were tested in 10-concentration IC50 mode with 3-fold serial dilution at a starting concentration of 10 ⁇ M.
  • DMSO control wells were included for reference.
  • a 10.8 nM (1.8X) MAGL mix in assay buffer was prepared, with 25 ⁇ L added to each reaction well, for a final assay concentration of 6 nM. No enzyme wells received 25 ⁇ L of buffer. Plate was incubated at room temperature for 30 minutes.35 mM solution of 4NPA in methanol was prepared daily.
  • a 4.5x 4NPA substrate solution was prepared in assay buffer and 10 ⁇ L was added to each reaction well, for a final assay concentration of 0.25 mM.
  • Table 5 provides potency measurements of MAGL inhibition measured using the Potency Assay above, with the following modifications described in Table C.
  • Example 20 Measuring FAAH Inhibition Potency (IC 50 )
  • Comparative compound potency at FAAH can be obtained with the following assay.
  • a “Selective MAGL Inhibitor Compound” refers to a compound that selectively inhibits MAGL with an IC 50 that is at least 10x the IC 50 for its inhibition of fatty acid amide hydrolase (FAAH), and that has an IC 50 of 150 nM or less for MAGL inhibition (according to the MAGL Potency assay of Example 19).
  • MAGL inhibitor compounds were also counter-screened for FAAH inhibition potency using the following assay. Assessment of FAAH inhibition was performed using Fatty Acid Amide Hydrolase Inhibitor Screening Assay Kit (Cayman Item No.
  • the kit utilizes human recombinant FAAH and the fluorescent substrate, AMC Arachidonoyl amide (AAMCA).5 ⁇ L of assay buffer (125 mM Tris, pH 9.0, 1 mM EDTA, i.e. ethylenediaminetetraacetic acid) was added to a 384-well black plate (Corning, 3573). Test compounds and control inhibitor JZL-195 (Cayman Chemical, 13668) were tested in 10-concentration IC50 mode with 3-fold serial dilution at a starting concentration of 100 ⁇ M and 10 ⁇ M, respectively.
  • assay buffer 125 mM Tris, pH 9.0, 1 mM EDTA, i.e. ethylenediaminetetraacetic acid
  • test compounds 300 nL or 30 nL of test compounds were delivered into a 384-well black plate (Corning, 3573) using a Labcyte Echo, followed by addition of 15 ⁇ L of FAAH enzyme (Cayman, 700302) in assay buffer. After a 5-minute pre-incubation at room temperature, 10 ⁇ L of AAMCA was added in assay buffer to start the reaction. Final concentration of FAAH enzyme is not specified and AAMCA substrate was used at the 20 uM. After these dilutions, the final concentration of the test compounds ranged from 100 ⁇ M to 5.08 nM or 10 ⁇ M down to 0.508 nM.
  • Example 21 Measuring Reversible MAGL Inhibition (IC 50 ) [000264] The reversible mechanism of MAGL inhibition of a test compound of Formula (I) can be determined. Flag-tagged MAGL enzyme will be immobilized on anti-Flag beads. Immobilized enzyme will be incubated +/- inhibitor at a dose that produces complete inhibition. Colorimetric substrate (4-NPA) will be added and the reaction monitored on a plate reader for 30 minutes to verify complete inhibition. Immobilized enzyme will then be washed thoroughly to remove the inhibitor, and fresh substrate will be added. The reaction will be monitored for an additional 30 minutes; returning enzymatic activity will indicate reversibility of inhibition.
  • Flag-tagged MAGL enzyme will be immobilized on anti-Flag beads. Immobilized enzyme will be incubated +/- inhibitor at a dose that produces complete inhibition. Colorimetric substrate (4-NPA) will be added and the reaction monitored on a plate reader for 30 minutes to verify complete inhibition. Immobilized enzyme will then be washed thoroughly to remove the inhibitor, and fresh
  • the effects of dilution and preincubation on the MAGL inhibitory activity of a compound can be evaluated using methods disclosed in J. Med. Chem. 2019, 62, 1932 ⁇ 1958, 1942.
  • the potency should not decrease after dilution, whereas for a reversible inhibition, the potency level should be strongly reduced after dilution. Therefore, the inhibition produced by incubation with a 4000 nM concentration of a test compound can be measured after a 40 ⁇ dilution and compared to the potency observed by a 4000 and a 100 nM of the test compound.
  • a reversible mechanism of inhibition can be identified when the inhibition produced by 100 nM of the test compound is similar to that obtained after a 40 ⁇ dilution and was considerably lower than that produced by the same compound at a concentration of 4000 nM.
  • the inhibition activity of a test compound can be measured at different preincubation times with MAGL.
  • the test compound can be preincubated with the enzyme for 0, 30, and 60 min before adding the substrate to start the enzymatic reaction.
  • An irreversible inhibition should produce a higher potency after longer incubation times, whereas a reversible inhibitor should produce a constant inhibition potency over all the different incubation times.
  • MAGL enzyme was incubated for 30 minutes in the presence of 40X the IC50 concentration of inhibitor. Enzyme + inhibitor mix was then diluted 40-fold so that the final concentration of the inhibitor equaled the IC 50 concentration. Substrate was added and the reaction was monitored for 30 minutes. For a reversible inhibitor, percent inhibition after dilution to the IC 50 concentration should be 50 + 15%.
  • the MAGL reversible inhibition assay of Example 21 above was performed to test reversibility of inhibition by compounds depicted in Table E.
  • Example 22A Pharmacokinetics and Estimation of 2-AG in Male C57BL/6 Mice Brain Following a Single Intraperitoneal Administration of a reversible MAGL inhibitor compound [Compound 74]
  • 2-Arachidonoylglycerol (2-AG) the major endogenous cannabinoid in the brain modulates neural excitability and decreases the synaptic hyperactivity associated with epileptic seizures.
  • Monoacylglycerol lipase degrades 2-AG in brain and inhibition of MAGL elevates 2-AG and reduces seizures in preclinical models of epilepsy.
  • 2-AG is dynamically coupled to seizure activity and is an excellent biomarker of the anticonvulsant activity of MAGL inhibition.
  • mice were euthanized by cervical dislocation and brain samples were dissected rapidly and snap frozen in liquid nitrogen, weighed and homogenized in 2 mL of acetonitrile containing 2-AGd5. Blood samples were centrifuged at 4000 rpm for 10 minutes at 4oC. Plasma was harvested and separated in pre-labeled tubes. All samples were stored below -70oC until bioanalysis. [000279] Analysis: Brain samples were processed for 2-AG estimation.2-AG levels were the detected values. Plasma concentrations were determined by fit for purpose LC-MS/MS method.
  • FIG.1A is a bar graph showing both the plasma and brain concentrations of Compound 7430 minutes after IP administration of 150 mg/kg of Compound 74 to the mouse model described above.
  • FIG.1B is a bar graph showing 2-AG measurement in the brain of the mouse model described above observed 30 minutes after the IP administration of 150 mg/kg of Compound 74.
  • FIG.2 is a scatter plot of brain 2-AG levels vs brain concentration of Compound 74.
  • FIG.3A is a graph showing the brain concentration after the administration of Compound 74 (50 mg/kg) and a comparator compound JZL-184 (40 mg/kg) in a mouse model.
  • FIG.3B is a graph showing the corresponding brain concentration of 2-AG after the administration of Compound 74 (50 mg/kg) and a comparator compound JZL-184 (40 mg/kg) in the animal model.
  • Example 22B Pharmacokinetics and Estimation of 2-AG in Male C57BL/6 Mice Brain Following a Single Intraperitoneal Administration of a reversible MAGL inhibitor compound
  • Compound 473 [000286] This experiment was performed to determine plasma pharmacokinetics and estimate 2-AG levels in male C57BL/6 mice brain following a single intraperitoneal administration of Compound-473 (Dose: 20 mg/kg).
  • Brain kp was found to be 1.44 following 20 mg/kg intraperitoneal dose administration. Following single intraperitoneal dose administration of Compound 473 at 20 mg/kg to male C57BL/6 mice, 2-AG concentrations were found to be 17.38 nmole/gram at 0.5 h. Following only vehicle (5% NMP, 5% Solutol HS15 and 90% Normal saline) administration intraperitoneally at 10 mL/kg dose volume, plasma concentrations were not detected in vehicle group whereas mean 2-AG concentrations in brain were found to be 4.17 nmole/gram at 0.5 h.
  • Table 19A Individual 2-AG concentration-time data following a single intraperitoneal administration of Compound 473 in male C57BL/6 mice (Dose: 20 mg/kg)
  • Table 19B Individual plasma and brain concentration-time data following a single intraperitoneal administration of Compound 473 in male C57BL/6 mice (Dose: 20 mg/kg)
  • Example 23 Pharmacokinetic Study of Compounds in Mice [000298] Healthy male C57BL/6 mice (8-12 weeks old) weighing between 17 to 35 g were procured from Global, India. Temperature and humidity were maintained at 22 ⁇ 3 oC and 30-70%, respectively and illumination was controlled to give a sequence of 12 hr light and 12 hr dark cycle.
  • Animals in Group 2 were administered orally with solution formulation of Compound 74 in 5% NMP, 5% Solutol HS-15 and 90% normal saline at 30 mg/kg dose.
  • Blood samples (approximately 60 ⁇ L) were collected under light isoflurane anesthesia from retro orbital plexus at 0.25, 0.5, 1, 2, 4 and 8 hr (IP and PO). Plasma samples were separated by centrifugation of whole blood and stored below -70 oC until bioanalysis.
  • animals were euthanized with excess CO2 and brain samples were collected from set of two mice at each time point. Brain samples were divided into two parts.
  • Half brain samples were homogenized using ice-cold phosphate buffer saline (pH-7.4) and homogenates were stored below -70 ⁇ 10 oC until analysis. Total homogenate volume was three times the brain weight. Other part of brain was stored below -70 ⁇ 10 oC for further analysis. All samples were processed for analysis by protein precipitation using acetonitrile and analyzed with fit-for-purpose LC/MS/MS method (LLOQ – 2.02 ng/mL for plasma and 6.06 ng/g for brain). Pharmacokinetic parameters were calculated using the non- compartmental analysis tool of Phoenix WinNonlin®.
  • Plasma samples were collected under light isoflurane anesthesia from two mice at 0.25, 0.5, 1, 2, 4 and 8 h. Plasma was harvested by centrifugation of blood and stored at -70 ⁇ 10 oC until analysis. After blood collection, brain was perfused and isolated at 0.25, 0.5, 1, 2, 4 and 8 h. Brain samples were dipped thrice in ice-cold phosphate buffer saline, blotted dry and cut in to two equal portion. Half -brain samples from each time-point were weighed and homogenized using ice-cold phosphate buffer saline with twice volume of brain weight making the total homogenate three volumes and stored below -70 ⁇ 10 oC until analysis.
  • the formulation vehicle used was 5 % v/v NMP, 5 % v/v Solutol HS-15 and 90 % v/v Normal saline.
  • Blood samples (approximately 60 PL) were collected under light isoflurane anesthesia (Surgivet®) from retro orbital plexus from a set of three mice at 0.25, 0.5, 1, 2, 4 and 8 h.
  • plasma was harvested by centrifugation at 4000 rpm, 10 min at 4 0 C and samples were stored at -70 ⁇ 10oC until bioanalysis.
  • animals were sacrificed followed by vena-cava was cut open and whole body was perfused from heart using 10 mL of normal saline.
  • the formulation vehicle used was 5 % v/v NMP, 5 % v/v Solutol HS-15 and 90 % v/v Normal saline.
  • Blood samples (approximately 60 PL) were collected under light isoflurane anesthesia (Surgivet®) from retro orbital plexus from a set of three mice at 0.25, 0.5, 1, 2, 4 and 8 h.
  • plasma was harvested by centrifugation at 4000 rpm, 10 min at 4 0 C and samples were stored at -70 ⁇ 10oC until bioanalysis.
  • whole body was perfused using 10 mL of normal saline. Brain samples were collected from set of three mice at 0.25, 0.5, 1, 2, 4 and 8 h.
  • brain samples were rinsed three times in ice cold normal saline (for 5-10 seconds/rinsed using ⁇ 5-10 mL normal saline in disposable petri dish for each rinse), dried on blotting paper and cut in to two equal portion.
  • Half -brain was used for PK estimation and half brain was snap freezed and stored below -70 ⁇ 10 oC.
  • Half brain (for PK estimation) was weighed and homogenized using ice-cold phosphate buffer saline with twice volume of brain weight making the total homogenate to three volumes and stored below -70 ⁇ 10 oC until analysis.
  • the formulation vehicle used was 5 % v/v NMP, 5 % v/v Solutol HS-15 and 90 % v/v Normal saline.
  • Blood samples (approximately 60 PL) were collected under light isoflurane anesthesia (Surgivet®) from retro orbital plexus from a set of three mice at 0.25, 0.5, 1, 2, 4 and 8 h.
  • plasma was harvested by centrifugation at 4000 rpm, 10 min at 4 0 C and samples were stored at -70 ⁇ 10oC until bioanalysis.
  • animals were sacrificed followed by vena-cava was cut open and whole body was perfused from heart using 10 mL of normal saline.
  • Table F Data obtained from Pharmacokinetic study of Example 23 [000304] Referring to the data in Table F, the C max is the peak concentration of a drug observed over time after a dose of the drug has been administered. Data presented in the table above demonstrate the ability of PSY compounds to enter the brain. AUC last is the area under the brain concentration-time curve to the last measured brain concentration. This reflects the total drug exposure over time after a dose has been administered.
  • Brain K p (C max ) is the ratio of the maximum observed concentrations of drug in the brain and plasma. Higher K p (C max ) values indicate more delivery of the drug to the brain.
  • Example 24 Measuring Efficacy of Compounds in PTZ and MES models.
  • Latency to seizure onset, seizure severity, frequency, and duration will be determined at a specific time period.
  • a compound disclosed herein is more effective than JZL184 and significantly diminish PTZ-induced seizure threshold and frequency, by 350% in the majority if not all the animals.
  • this example describes assessing a compound disclosed herein in the maximal electroshockseizure (MES) mouse model.
  • MES maximal electroshockseizure

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Abstract

L'invention concerne des procédés d'utilisation d'inhibiteurs de monoacylglycérol lipase (MAGL) réversibles pour le traitement d'états neurologiques tels que l'épilepsie.
PCT/US2024/036852 2023-07-06 2024-07-05 Inhibiteurs de monoacylglycérol lipase et leur utilisation pour le traitement de troubles neurologiques Pending WO2025010392A2 (fr)

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