Monoacylglycerol lipase modulators
AssigneeJanssen Pharmaceutica NV
InventorsMichael K. Ameriks, Gang Chen, Chaofeng Huang, Brian Ngo Laforteza, Suchitra Ravula, Emma Helen Southgate, Wei Zhang
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Abstract
Fused compounds of Formula (I) and Formula (II), pharmaceutical compositions containing them, methods of making them, and methods of using them including methods for treating disease states, disorders, and conditions associated with MGL modulation, such as those associated with pain, psychiatric disorders, neurological disorders (including, but not limited to major depressive disorder, treatment resistant depression, anxious depression, bipolar disorder), cancers and eye conditions. Wherein R1, R2, R2a, R3, R3a, R4, and R4a are defined herein.
Claims8
A method of treating a subject suffering from or diagnosed with a disease, disorder, or condition treatable by inhibition of MGL receptor activity, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one compound of Formula (I):
- wherein:
- R2 is selected from the group consisting of:
- (a)
- (b) pyridyl substituted with OC1-4 haloalkyl;
- (c) pyrazole or 1H-1,2,4-triazole each substituted with one or two members each independently selected from the group consisting of:
- H, Cl, C1-4 alkyl, cyclopropyl and phenyl;
- (d)
- (e)
- (f)
- and
- (g)
- where X is selected from the group consisting of:
- O, S, NH, and NCH3;
- Ra is H or halo;
- Rb is selected from the group consisting of:
- H, halo and CH3;
- Rc is H or CF3;
- and
- Rd is H or CH3;
- R3 is selected from the group consisting of:
- (h) Phenyl;
- or phenyl independently substituted with one or two members selected from the group consisting of:
- halo and OC1-4 haloalkyl;
- (i)
- and
- (j) C3-4cycloalkyl;
- and
- R4 is selected from the group consisting of:
- C1-4 alkyl;
- with the proviso that when R2 is
- then R3 is cyclopropyl;
- and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers of compounds of Formula (I).
A method of treating a subject suffering from or diagnosed with a disease, disorder, or condition treatable by inhibition of MGL receptor activity, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one compound of Formula (II):
- wherein
- R1 is C1-4 alkyl;
- R2a is selected from the group consisting of:
- (a)
- (b) 6-Membered heteroaryl selected from the group consisting of:
- (c) 5-Membered heteroaryl selected from the group consisting of:
- (d) 5,6-Fused or 6,5-fused heteroaryl selected from the group consisting of:
- (e) Fused 6,6 heteroaryl selected from the group consisting of:
- and
- (f) Heterocycloalkyl selected from the group consisting of:
- R3a is selected from the group consisting of:
- (g) Phenyl;
- or phenyl substituted with one, two, or three members each independently selected from the group consisting of:
- halo, C1-4 alkyl, C1-4 haloalkyl, OC1-4 alkyl, and OC1-6 haloalkyl;
- (h) 5-Membered heteroaryl selected from the group consisting of:
- (i) 6-Membered heteroaryl selected from the group consisting of:
- (j) 5,6-Fused or 6,5-fused heteroaryl selected from the group consisting of:
- and
- (k) Heterocycloalkyl selected from the group consisting of:
- Re is selected from the group consisting of:
- OC1-4 alkyl, OC1-4 haloalkyl, (C═O) NHCH3, and 5-membered heteroaryl ring containing two or three nitrogen members, wherein the 5-membered heteroaryl ring is optionally substituted with one Rf member;
- Rf is selected from the group consisting of:
- H, halo, C1-4 alkyl, C1-4 haloalkyl, OC1-4 alkyl, and OC1-4 haloalkyl;
- Rg is selected from the group consisting of:
- OC1-4 alkyl, OC1-4 haloalkyl, CH2OCH3, CH2OH,
- Rh is selected from the group consisting of:
- H, C1-4 alkyl, C1-4 haloalkyl, and C3-6cycloalkyl;
- Ri is selected from the group consisting of:
- H, halo, C1-4 alkyl, C1-4 haloalkyl, OC1-4 alkyl, C3-6cycloalkyl, and C3-6cycloalkyl substituted with one or two members independently selected from:
- F and CH3;
- Rj is selected from the group consisting of:
- H, halo, C1-4 alkyl and C1-4 haloalkyl;
- Rk is selected from the group consisting of:
- H, halo, OH, C1-4 alkyl, C1-4 haloalkyl, OC1-4 alkyl, and OC1-4 haloalkyl;
- Rm is H or C1-4 alkyl;
- Rn is selected from the group consisting of:
- H, halo and OC1-4 alkyl;
- Ro is selected from the group consisting of:
- H, C1-4 alkyl, and C1-4 haloalkyl;
- Rp is selected from the group consisting of:
- H, C1-4 alkyl, and OC1-4 alkyl;
- Y is CH or N;
- and
- R4a is selected from the group consisting of:
- CH3, CF2H, CF3, C3-6cycloalkyl, and phenyl;
- and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers of compounds of Formula (II).
Dependencies are inferred from the claim text.