Radiolabeled monoacylglycerol lipase occupancy probe

A radiolabeled monoacylglycerol lipase (MGLL) occupancy probe, comprising an MGLL inhibitor containing a positron emission tomography (PET) tracer radionuclide, wherein the MGLL inhibitor has the structure of Formula (I):

• wherein
• T is CX3 or
• X is selected independently, for each occurrence, from H, F, Cl or Br;
• wherein at least three occurrences of X are F;
• V is O or NRa;
• RV is selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C3-6cycloalkyl, phenyl, heteroaryl, and heterocyclyl, or when Ra and Rv occur together with the nitrogen to which they are attached, form a 4-6 membered heterocyclic ring which may have an additional heteroatom selected from O, S, and N;
• wherein C1-C6alkyl, C2-C6alkenyl, phenyl, heterocyclic ring and heterocyclyl are optionally substituted by one, two, or three moieties independently selected from the group consisting of halogen, hydroxyl, C1-C6alkyl, cyano, and phenyl;
• and
• wherein
• a)
• R1 and R2 taken together with the nitrogen to which they are attached form a moiety selected from:
• a 4-7 membered heterocyclic ring B having an additional nitrogen;
• or
• a 4-7 membered heterocyclic ring A;
• wherein one carbon of ring A has a substituent represented by:
• L2 is C1-C6alkylene or C1-C6alkylene-NRa—;
• R3 and R5 are each independently selected from phenyl, naphthyl, a mono or bicyclic heteroaryl and a mono or bicyclic heterocycle, wherein the heterocycle or heteroaryl has 1, 2 or 3 heteroatoms independently selected from O, S, and N;
• and wherein R3 and R5 may be independently and optionally substituted by one, two, three, or four moieties each independently selected from Rg;
• R4 is selected from the group consisting of H, halogen, hydroxyl, cyano, and C1-C5alkoxy;
• A is optionally substituted on another carbon by one, two, three, or four substituents each independently selected from Rd;
• the additional nitrogen of ring B has a substituent represented by:
• L3 is selected from the group consisting of:
• a bond, C1-C6alkylene, —C(O)—, C1-C6alkylene-C(O)—, C(O)—C1-C6alkylene-, NRa—C(O)—C1-C6alkylene-, C1-C6alkylene-O—C(O)—, —S(O)w—, and C1-C6alkylene-S(O)w—, wherein w is 0, 1, or 2, and wherein C1-C6alkylene is optionally substituted by one or two substituents selected from the group consisting of:
• halogen, hydroxyl, cyano, and an additional R7, wherein when L3 is —S(O)w—, then R7 is not H;
• R7 is selected from the group consisting of:
• H, phenyl, naphthyl, mono or bicyclic heteroaryl, and mono or bicyclic heterocyclyl, wherein the heteroaryl or the heterocyclyl has 1, 2 or 3 heteroatoms independently selected from O, S, and N;
• wherein R7 is optionally substituted by one, two, three, or four moieties independently selected from Rh;
• B is optionally substituted on one or more carbons by one, two, three, or four moieties each independently selected from Rd;
• or
• b)
• R1 is-L1-R6;
• R2 is H or C1-C6alkyl;
• L1 is C1-C6alkylene or a bond;
• R6 is selected from the group consisting of phenyl, naphthyl, a mono or bicyclic heteroaryl, and a mono or bicyclic heterocycle, wherein the heteroaryl or heterocycle has 1, 2 or 3 heteroatoms independently selected from O, S, and N;
• and R6 is optionally substituted by one, two, three, or four moieties independently selected from the group consisting of:
• halogen, phenyl (optionally substituted by one, two, or three moieties independently selected from Rc), phenyloxy (optionally substituted by one, two, or three moieties independently selected from Rc), anilinyl (optionally substituted on a carbon by one, two or three moieties independently selected from Rc), hydroxyl, cyano, C1-6alkyl (optionally substituted by cyano, hydroxyl, or one, two, or three halogens), C1-6alkoxy (optionally substituted by cyano, hydroxyl, or one, two, or three halogens), RaRbN—, RaRbN—SO2—, RaRbN—C(O)—, C1-6alkyl-C(O)NRa—, Ra—S(O)w—, Ra—S(O)w—NRb— (wherein w is 0, 1, or 2), heteroaryl (optionally substituted by one, two, or three moieties independently selected from Rc), and heteroaryloxy;
• Ra and Rb may be independently selected, for each occurrence, from the group consisting of hydrogen and C1-3alkyl;
• wherein C1-3alkyl may optionally be substituted by one or more substituents selected from halogen, cyano, oxo, hydroxyl, heterocycle, and phenyl;
• or Ra and Rb, when they occur together with the nitrogen to which they are attached, form a 4-6 membered heterocyclic ring or a 9-10 membered bicyclic heterocycle or spirocyclic ring, which may have an additional heteroatom selected from O, S, and N;
• wherein the 4-6 membered heterocyclic ring or 9-10 membered bicyclic heterocycle or spirocycle may optionally be substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, C1-6alkyl, C1-6haloalkyl, —S(O)w—C1-6alkyl (where w is 0, 1, or 2), hydroxyl, —C(O)—C1-6alkyl, —NH2, and —NH—C(O)—C1-6alkyl;
• Rc is selected from the group consisting of halogen, cyano, hydroxyl, nitro, C1-6alkyl (optionally substituted by one, two, or three halogens, cyano, or hydroxyl), C2-6alkenyl (optionally substituted by one, two, or three halogens), C2-6alkynyl (optionally substituted by one, two, or three halogens), C3-6cycloalkyl, C1-6alkoxy (optionally substituted by one, two, or three halogens), RaRbN—, RaRbN—SO2—, RaRbN—C(O)—, Ra—C(O)—NRa—, Ra—C(O)—, Ra—S(O)w—NRb— (wherein w is 0, 1, or 2), and Ra—S(O)w— (wherein w is 0, 1, or 2);
• Rd is selected from the group consisting of:
• H, C1-6alkyl (optionally substituted by one, two, or three halogens, or hydroxyl) and RaRbN—C(O)—;
• Rg is selected from the group consisting of:
• halogen, phenyl, phenyloxy, anilinyl, hydroxyl, cyano, C1-6alkyl (optionally substituted by cyano, hydroxyl, or one, two, or three halogens), C3-6cycloalkyl (optionally substituted by cyano, hydroxyl, or one, two, or three halogens), C2-6alkenyl (optionally substituted by cyano, hydroxyl, or one, two, or three halogens), C2-6alkynyl (optionally substituted by cyano, hydroxyl, or one, two, or three halogens), C1-6alkoxy (optionally substituted by cyano, hydroxyl, or one, two, or three halogens), Ra—C(O)NRa—, RaRbN—, RaRbN—SO2—, Ra—S(O)w— (wherein w is 0, 1, or 2), Ra—SO2—NRb—, RaRbN—C(O)—, heterocycle (optionally substituted by one, two, or three moieties each independently selected from Rc, and connected to R3 or R5 through a carbon or heteroatom), and heteroaryl (optionally substituted by one, two, or three moieties each independently selected from Rc, and connected to R3 or R5 through a carbon or heteroatom), or two adjacent Rg groups, along with the carbons to which they are attached, can be taken together to form a 5- or 6-member heterocyclic or heteroaryl ring optionally substituted with 0, 1 or 2 halogens selected from F or Cl and which may have one or two additional heteroatoms selected from O, S, and N;
• Rh is selected from the group consisting of:
• halogen, phenyl (optionally substituted by one, two, or three moieties each independently selected from Rc), phenyloxy (optionally substituted by one, two, or three moieties each independently selected from Rc), hydroxyl, cyano, C1-6alkyl (optionally substituted by cyano, hydroxyl, or one, two, or three halogens), C2-6alkenyl (optionally substituted by cyano, hydroxyl, or one, two, or three halogens), C2-6alkynyl (optionally substituted by cyano, hydroxyl, or one, two, or three halogens), C1-6alkoxy (optionally substituted by cyano, hydroxyl, or one, two, or three halogens), RaRbN—, Ra—C(O)NRa—, RaRbN—SO2—, RaRbN—C(O)—, Ra—S(O)w— (wherein w is 0, 1, or 2), Ra—SO2—NRb—, heteroaryl (optionally substituted by one, two, or three moieties each independently selected from Rc, and connected to R7 through a carbon or heteroatom), heterocycle (optionally substituted by one, two, or three moieties each independently selected from Rc, and connected to R7 through a carbon or heteroatom), and heteroaryloxy (optionally substituted by one, two, or three moieties each independently selected from Rc), or two adjacent Rh groups, along with the carbons to which they are attached, can be taken together to form a 5- or 6-member heterocyclic or heteroaryl ring optionally substituted with 0, 1 or 2 halogens selected from F or Cl and which may have one or two additional heteroatoms selected from O, S, and N;
• or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

A compound having the structure of Formula (V):

• wherein
• p is 0, 1, or 2;
• Rd is H or C1-6alkyl;
• L3 is a bond, —CH2—, —S(O)2—, or —C(O)—;
• R7 is phenyl substituted by RaRbN— and a moiety selected from the group consisting of:
• halogen and C1-6alkyl (optionally substituted by one, two, or three halogens);
• Ra and Rb, together with the nitrogen to which they are attached, form a 4-6 membered heterocyclic ring or a 9-10 membered bicyclic heterocycle or spirocyclic ring, which may have an additional heteroatom selected from O, S, and N;
• wherein the 4-6 membered heterocyclic ring or 9-10 membered bicyclic heterocycle or spirocycle is substituted by C1-6haloalkyl;
• or a solvate, hydrate, tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.