US 7,517,874 B2
Substituted imidazo[1,5-a][1,4]diazepines and imidazo[1,5-a]pyrazines as cannabinoid receptor agonists for the treatment of pain
R. Paul Beckett, Yorktown Heights, N.Y. (US); Richard Foster, Bude (United Kingdom); Christelle Henault, Bude (United Kingdom); Janet L. Ralbovsky, Shelton, Conn. (US); Carla M. Gauss, White Plains, N.Y. (US); Gary G. Gustafson, Ridgefield, Conn. (US); Zhiyong Luo, New City, N.Y. (US); Ann-Marie Campbell, Monroe, Conn. (US); and Tatiana E. Shelekhin, Ridgefield, Conn. (US)
Assigned to Cara Therapeutics, Inc., Shelton, Conn. (US)
Filed on Jun. 20, 2008, as Appl. No. 12/142,846.
Claims priority of provisional application 60/936754, filed on Jun. 21, 2007.
Claims priority of provisional application 60/994422, filed on Sep. 19, 2007.
Claims priority of provisional application 61/008395, filed on Dec. 19, 2007.
Prior Publication US 2008/0318935 A1, Dec. 25, 2008
Int. Cl. A61K 31/519 (2006.01); C07D 487/04 (2006.01); A61P 25/02 (2006.01)
U.S. Cl. 514—221  [514/249; 544/230; 544/350; 540/543; 540/568] 20 Claims
 
1. A compound having the structure of formula I:

OG Complex Work Unit Drawing
or a pharmaceutically acceptable salt, acid salt or stereoisomer thereof, wherein:
Y is selected from the group consisting of NRa and N+R1R2 X−;
Z is selected from the group consisting of a bond, —(CH2)p, —CH═CH—, —C≡C—, and —CO—;
Ra is selected from the group consisting of —H, C1-C8 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, —SO2R3, —COR3, —CONR3R4, —CSNR3R4, —COOR3 and —(CH2)qheterocyclyl, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl of Ra are each optionally substituted with one to four substituents independently selected from the group consisting of halo, —OH, oxo, —NH2, —NO2, —CN, —COOH, —COR3, —OCF3, —CF3, C1-C6 alkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, phenyl, trifluoromethoxy and trifluoromethyl;
Rb is selected from the group consisting of C1-C8 alkyl, C2-C8 alkenyl, aryl, —NR5R6,

OG Complex Work Unit Drawing
and

OG Complex Work Unit Drawing
wherein the alkyl, alkenyl and aryl of Rb are each optionally substituted with one to three substituents independently selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C4 alkoxy, aryl, 5-, 6-, and 7-membered heterocyclyl, halo, —OH, —NH2, —CN and —NO2;
Rc is selected from the group consisting of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C3-C8 cycloalkenyl, C1-C4 alkoxy, aryl, 5-, 6-, 7-, and 8-membered monocyclic heterocyclyl, 9-, and 10-membered bicyclic heterocyclyl; wherein the alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C3-C8 cycloalkenyl, aryl, 5-, 6-, 7-, 8-membered monocyclic heterocyclyl and 9- and 10-membered bicyclic heterocyclyl of Rc are optionally substituted with one to five substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl, C4-C8 cycloalkenyl, halo, —OH, —NH2, (A)(A′)(A″)(A′″)aryl, (A)(A′)(A″)(A′″)heterocyclyl, NR14R15, (CH2)pNR14R15, —CN, —NO2, oxo, —COOR14, SOR14, SO2R14, SO2NR14R15, NR15SO2R16, COR14, CONR14R15 and NR15COR16; wherein (A), (A′), (A″) and (A′″) are each an independently selected from the group consisting of —H and C1-C4 alkyl and each heterocyclyl of (A)(A′)(A″)(A′″)heterocyclyl is independently selected from the group consisting of 5-, 6-, 7- and 8-membered monocyclic heterocyclyl and 9- and 10-membered bicyclic heterocyclyl;
R1 and R2 are each independently C1-C4 alkyl;
R3 and R4, when either or both are present, are each independently selected from the group consisting of —H, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, 4-, 5-, 6-, 7- and 8-membered heterocyclyl; wherein R3 and R4 that are not H are each independently optionally substituted with one to three substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C1-C4 alkoxy, C1-C4 acyl, aryl, 5-, 6-, 7- and 8-membered monocyclic heterocyclyl, and 9- and 10-membered bicyclic heterocyclyl, —NH2, —NO2, —CN, —OH, —COOH, oxo, and halo; provided that if Ra is SO2R3, then R3 is not —H; alternatively, R3 and R4 taken together with the nitrogen atom to which they are bonded form a heterocyclyl selected from the group consisting of 4-, 5-, 6-, 7- and 8-membered heterocyclyl;
R5 is selected from the group consisting of —H, C1-C4 alkyl and C1-C4 haloalkyl; wherein the alkyl and haloalkyl of R5 are optionally substituted with one to four substituents independently selected from the group consisting of C1-C4 alkoxy, —OH, —NH2 and —CN;
R6 is selected from the group consisting of —H, —CR10R11R12, —CR10R11COR13, C1-C8 alkyl, C3-C10 cycloalkyl, aryl, 5-, 6-, 7-, 8-membered monocyclic heterocyclyl, and 9-, 10-membered bicyclic heterocyclyl; wherein the alkyl, cycloalkyl, aryl, and heterocyclyl of R6 are optionally substituted with one to three substituents independently selected from the group consisting of C1-C4 alkyl, aryl, halo, —OH, C1-C4 alkoxy, C1-C4 hydroxyalkyl, —COR13, —SO2R11, —SO2NR8R9, —NH2, —CN and —NO2; alternatively, R5 and R6 taken together with the nitrogen atom to which they are bonded form a heterocyclyl selected from the group consisting of 5-, 6-, 7- and 8-membered monocyclic heterocyclyl, and 9- and 10-membered bicyclic heterocyclyl, which heterocyclyl substituent of R6 is optionally substituted with one to two substituents independently selected from the group consisting of —CONR1R2 and oxo;
R7 is selected from the group consisting of-COR3, —COOR3, —SO2R3, and 5-, 6- and 7-membered heterocyclyl;
R8 and R9 are independently selected from the group consisting of —H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C2-C4 alkenyl, C3-C6 cycloalkyl, aryl, 5-, 6-, 7- and 8-membered monocyclic heterocyclyl, and 9- and 10-membered bicyclic heterocyclyl, halo, —OH, —CONH2, —NH2, —CN and —NO2; alternatively: (i)R8 and R9, taken together with the nitrogen atom to which they are bonded form a heterocyclyl ring which is optionally substituted with one to three substituents selected from the group consisting of C1-C4 alkyl, halo, oxo and aryl; or (ii) R8 and R9, taken together with the carbon atom to which they are bonded form a cycloalkyl which is optionally substituted with one to three substituents selected from the group consisting of C1-C4 alkyl, halo, oxo and aryl;
R10 is selected from the group consisting of —H and C1-C4 alkyl;
R11 is selected from the group consisting of —H, C1-C8 alkyl, C2-C6 alkenyl, C2-C4 alkynyl, C3-C10 cycloalkyl, aryl, 5-, 6-, 7- and 8-membered monocyclic heterocyclyl, and 9- and 10-membered bicyclic heterocyclyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl and 5-, 6-, 7- and 8-membered monocyclic heterocyclyl, and 9- and 10-membered bicyclic heterocyclyl of R11 are optionally substituted with one to three substituents independently selected from the group consisting of C1-C4 alkyl, C3-C6 cycloalkyl, aryl, and 5-, 6-, 7- and 8-membered monocyclic heterocyclyl, and 9- and 10-membered bicyclic heterocyclyl, halo, —OH, C1-C4 alkoxy, —NH2, -guanidino, —CN, —NO2, oxo, —COOR10, —CONR8R9, —SO2NR8R9, —SR10, —SOR1 and —SO2R1;
R12 is selected from the group consisting of —H, C1-C4 alkyl and C1-C4 hydroxyalkyl;
R13 is selected from the group consisting of —OR10 and —NR8R9;
R14, R15 and R16 are each independently selected from the group consisting of —H, and C1-C4 alkyl; alternatively, R14 and R15 taken together with the nitrogen atom to which they are bonded form a heterocyclyl selected from the group consisting of 5-, 6-, 7- and 8-membered monocyclic heterocyclyl, and 9- and 10-membered bicyclic heterocyclyl;
X− is an anionic counterion;
m is an integer selected from 1 and 2; p is an integer from 1 to 6; and q is zero or an integer from 1 to 4; and
provided that when Rc is heterocyclyl, the heterocyclyl is directly bonded through a carbon atom of a ring of the heterocyclyl.