US 11,702,408 B2
5-membered aza-heterocyclic containing delta-opioid receptor modulating compounds, methods of using and making the same
Aimee Crombie Speerschneider, Chesterbrook, PA (US); Dennis Shinji Yamashita, Chesterbrook, PA (US); Philip Michael Pitis, Chesterbrook, PA (US); Michael John Hawkins, Chesterbrook, PA (US); Guodong Liu, Chesterbrook, PA (US); Tamara Ann Miskowski Daubert, Chesterbrook, PA (US); Catherine C. K. Yuan, Chesterbrook, PA (US); Robert Borbo Kargbo, Chesterbrook, PA (US); Robert Jason Herr, Chesterbrook, PA (US); and Donna Romero, Chesterbrook, PA (US)
Assigned to TREVENA, INC., Chesterbrook, PA (US)
Appl. No. 16/486,541
Filed by Trevena, Inc., Chesterbrook, PA (US)
PCT Filed Feb. 15, 2018, PCT No. PCT/US2018/018312
§ 371(c)(1), (2) Date Aug. 16, 2019,
PCT Pub. No. WO2018/152293, PCT Pub. Date Aug. 23, 2018.
Claims priority of provisional application 62/460,407, filed on Feb. 17, 2017.
Prior Publication US 2021/0061790 A1, Mar. 4, 2021
Int. Cl. C07D 403/12 (2006.01); C07D 403/14 (2006.01); A61P 25/22 (2006.01); A61P 25/24 (2006.01); A61P 25/06 (2006.01); A61P 29/00 (2006.01)
CPC C07D 403/12 (2013.01) [A61P 25/06 (2018.01); A61P 25/22 (2018.01); A61P 25/24 (2018.01); A61P 29/00 (2018.01); C07D 403/14 (2013.01)] 14 Claims
 
1. A compound having Formula I,

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
Z2 is absent or Z2 is C1-C3 alkylene;
R12 is H, halo, —SO2C1-C6 alkyl, —OCF3, —OR16, —NR33S(═O)2R22, —(CH2)y-R17, —NH—(CH2)y-R17, —S—(CH2)y-R17, —O—(CH2)y-R17, or

OG Complex Work Unit Chemistry
R23 is H, —SO2C1-C6 alkyl, —OCF3, halo, optionally substituted C1-C6 alkyl, optionally substituted sulfonamide, or C(═O)R8;
or R12 and R23 form a 5-7 membered heterocycle that is fused to the phenyl ring;
each R8 is independently H, halo, C1-C6 haloalkyl, —C(═O)C1-C6 alkyl, —OR8A, S(O)2R8B, —(CH2)pR8c, optionally substituted 5-7 membered heterocycle, or optionally substituted C1-C6 branched or unbranched alkyl or —(CH2)pOR9, wherein R8A, R8B, and R8C are each, independently, H, optionally substituted C6-C10 aryl, optionally substituted C1-C6 haloalkyl, —NR20R21, optionally substituted C1-C6 branched or unbranched alkyl, optionally substituted C2-C6 alkenyl, —(CH2)pOR8D, optionally substituted cycloalkyl, —OH, optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl, or optionally substituted piperidyl, wherein R8D is independently, H, —C(═O)R8E, optionally substituted C1-C6 haloalkyl, optionally substituted nitrogen, optionally substituted C1-C6 branched or unbranched alkyl, optionally substituted C6-C10 aryl, optionally substituted 5-7 membered heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted cycloalkyl, optionally substituted 5-7 membered heterocycle, —OH, optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted phenyl, optionally substituted pyrrolidinyl, optionally substituted imidazolidinyl, optionally substituted morpholinyl, or optionally substituted piperidyl;
R8E is phenyl or C1-C6 branched or unbranched alkyl;
R13 is optionally substituted C6-C10 aryl, optionally substituted C1-C6 haloalkyl, —R20R21, optionally substituted C1-C8 branched or unbranched alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 haloalkenyl, optionally substituted C2-C6 haloalkenyl, —(CH2)nR19, optionally substituted cycloalkyl, including but not limited to cyclopropyl, optionally substituted C1-C6 alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl, optionally substituted pyridyl, optionally substituted piperidyl or C3-C6 cyclic ether;
R14 is optionally substituted C1-C6 branched or unbranched alkyl;

OG Complex Work Unit Chemistry
R16 is optionally substituted C1-C6 branched or unbranched alkyl, —CH2CH2OMe, or —CH2CH2R71, wherein R71 is a 5-7 membered heteroaryl or heterocycle;
R17 is H, C1-C6 haloalkyl, —OR18,

OG Complex Work Unit Chemistry
optionally substituted cycloalkyl, —(CH2)pR19, —C(═O)R19, or optionally substituted 5-7 membered heterocycle;
R18 is H, optionally substituted C6-C10 aryl, optionally substituted C1-C6 haloalkyl, —NR20R21, optionally substituted C1-C6 branched or unbranched alkyl, optionally substituted C2-C6 alkenyl, —(CH2)vR19, optionally substituted cycloalkyl, —OH, optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl, or optionally substituted piperidyl;
each R19 is, independently, H, optionally substituted C1-C6 haloalkyl, —NR20R21, optionally substituted C1-C6 branched or unbranched alkyl, optionally substituted C6-C10 aryl, optionally substituted 5- to 7-membered heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted cycloalkyl, optionally substituted 5-7 membered heterocycle, —OH, optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl, optionally substituted piperidyl; optionally substituted pyrrolidinyl, or optionally substituted imidazolidinyl,
R20 and R21 are, each, independently, H, optionally substituted C6-C10 aryl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 branched or unbranched alkyl, optionally substituted C2-C6 alkenyl, —(CH2)wR19, optionally substituted cycloalkyl, —OH, optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl, or optionally substituted piperidyl; or R20 and R21 together form a 5-7 membered optionally substituted heterocycle or a 5-7 membered optionally substituted heteroaryl with the atom to which R20 and R21 are bonded to;
each R22 is, independently, H or optionally substituted C1-C6 alkyl;
R24 is H, halo, optionally substituted C1-C6 alkyl;
R68 is H or optionally substituted C1-C6 alkyl;
R69 is H or optionally substituted C1-C6 alkyl or R24 or R69 form a C3-C6 cycloalkyl including the carbon to which R24 or R69 are bound to;
R33 is H or optionally substituted C1-C6 alkyl;
n is an integer from 0-6;
y is an integer from 0-6;
p is an integer from 0-6;
v is an integer from 0-6; and
each w is an integer from 0-6,
wherein each optionally substituted substituent is, independently, optionally substituted with a substituent selected from the group consisting of C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, phenyl, C1-C6alkoxy, C3-C5heteroaryl, C3-C6cycloalkyl, C5-C6aryloxy, —CN, —OH, oxo, halo, haloalkyl, —NO2, —CO2H, —NH2, —NH(C1-C8alkyl), —N(C1-C8alkyl)2, —NH(C6aryl), —N(phenyl)2, —CHO, —CO(C1-C6alkyl), —CO((phenyl), —CO2((C1-C6)alkyl), and —CO2(phenyl).