US 12,145,909 B2
N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[C]pyrrole negative allosteric modulators of NR2B
David R. Anderson, Salem, CT (US); Robert A. Volkmann, Mystic, CT (US); and Frank S. Menniti, Mystic, CT (US)
Assigned to Novartis AG, Basel (CH)
Filed by NOVARTIS AG, Basel (CH)
Filed on May 3, 2022, as Appl. No. 17/735,386.
Application 17/735,386 is a continuation of application No. 16/991,684, filed on Aug. 12, 2020, abandoned.
Application 16/991,684 is a continuation of application No. 16/255,500, filed on Jan. 23, 2019, granted, now 10,781,174, issued on Sep. 22, 2020.
Application 16/255,500 is a continuation of application No. 15/506,592, granted, now 10,239,835, issued on Mar. 26, 2019, previously published as PCT/US2015/051694, filed on Sep. 23, 2015.
Claims priority of provisional application 62/056,284, filed on Sep. 26, 2014.
Prior Publication US 2022/0274925 A1, Sep. 1, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/403 (2006.01); A61P 25/00 (2006.01); A61P 25/16 (2006.01); A61P 25/22 (2006.01); A61P 25/24 (2006.01); A61P 25/28 (2006.01); C07D 209/52 (2006.01); C07D 401/06 (2006.01); C07D 401/12 (2006.01); C07D 401/14 (2006.01); C07D 403/06 (2006.01); C07D 403/12 (2006.01)
CPC C07D 209/52 (2013.01) [A61P 25/00 (2018.01); A61P 25/16 (2018.01); A61P 25/22 (2018.01); A61P 25/24 (2018.01); A61P 25/28 (2018.01); C07D 401/06 (2013.01); C07D 401/12 (2013.01); C07D 401/14 (2013.01); C07D 403/06 (2013.01); C07D 403/12 (2013.01)] 21 Claims
 
1. A method of treating an emotional disorder selected from general anxiety disorder, social anxiety disorder, a phobia, and panic disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,
wherein:
L1 is straight or branched C1-C5 alkylene substituted with OH;
R1 is cycloalkyl, aryl, or heteroaryl, any of which is optionally substituted with one or more substituents selected from the group consisting of OH, CN, halogen, —C1-C6alkylaryl, —O—C1-C6alkylaryl, O—R10, OPO3−2M2, OP(O)(OH)2, SH, S—R10, C1-C5 straight or branched alkyl, NH2, NHR10, NHS(O)2R10, N(R10)(R10′), and NHCOR10, where M is a monovalent metal cation;
each R10 and R10′ is independently selected from the group consisting of H; C1-C6 alkyl optionally substituted with one or more substituents selected from the group consisting of OH, O—C1-C5 alkyl, OPO3−2M2, OP(O)(OH)2, OC(O)-alkyl, and OC(O)O-alkyl where M is a monovalent metal cation; and cycloalkyl optionally substituted with one or more substituents selected from the group consisting of OH and O—C1-C5 alkyl provided that no more than one oxygen is attached to any carbon; or R10 and R10′, together with the nitrogen to which R10 and R10′ are attached, form a heterocycle selected from the group consisting of oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl;
X is selected from O, S, —S(O)—, and —S(O)2—;
Y and Y′ are independently H, halogen, or C1-C5 alkyl;
L2 is a bond, —(CH2)n—, or —(CHR11)n—;
each Rn is independently selected from the group consisting of H, —C1-C5 alkylenyl-, —CO—C1-C5alkylenyl-, and -alkylenyl-CO-alkylenyl-;
R2 is phenyl, naphthyl, heteroaryl, or bicyclic heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, OH, C1-C6alkyl, OR10, CN, NH2, NHR10, N(R10)(R10′), -nitro, SH, SR10, SOR10, SO2R10, SO2NHR10, SO2N(R10)(R10′), CONH2, CONR10, and CON(R10)(R10′); and
n is 1, 2, or 3;
wherein cycloalkyl is a monocyclic saturated carbon ring containing 3-18 carbon atoms; and
wherein heteroaryl is a monocyclic, bicyclic, or polycyclic aromatic radical of 5 to 10 ring atoms and containing one or more ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, and when containing two fused rings, the aryl groups optionally have an unsaturated or partially saturated ring fused with a fully saturated ring.