US 11,912,713 B2
7-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)
Filed by Trevena, Inc., Chesterbrook, PA (US)
Filed on Nov. 22, 2021, as Appl. No. 17/532,413.
Application 17/532,413 is a continuation of application No. 16/486,539, granted, now 11,225,487, previously published as PCT/US2018/018303, filed on Feb. 15, 2018.
Claims priority of provisional application 62/460,386, filed on Feb. 17, 2017.
Prior Publication US 2022/0348588 A1, Nov. 3, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 487/08 (2006.01); A61P 25/22 (2006.01); A61P 23/00 (2006.01); A61P 25/24 (2006.01); C07D 223/04 (2006.01); C07D 403/12 (2006.01); C07D 403/14 (2006.01); C07D 405/14 (2006.01); C07D 417/14 (2006.01)
CPC C07D 487/08 (2013.01) [A61P 23/00 (2018.01); A61P 25/22 (2018.01); A61P 25/24 (2018.01); C07D 223/04 (2013.01); C07D 403/12 (2013.01); C07D 403/14 (2013.01); C07D 405/14 (2013.01); C07D 417/14 (2013.01)] 17 Claims
 
1. A compound having Formula I, Ia, Ia-1, or Ia-2,

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or a pharmaceutically acceptable salt thereof, wherein:

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is independently, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted imidazole,

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X1 is CH or N;
X2 is C, CH, or N provided that both X1 and X2 are not the same;
Y is O or NH;
R1 is H, —SO2C1-C6alkyl, —OCF3, halo, —NR30R31, —NH—(CH2)y—R17, —S—(CH2)y—R17, —(CH2)y—R17,
—O—(CH2)y—R17,—OR8, or

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R17 is H, C1-C6 haloalkyl, —OR18,

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—C(═O)N(R18)2, optionally substituted cycloalkyl, —(CH2)pR19, or optionally substituted heterocycle;
R23 is H, halo, —SO2C1-C6alkyl, —OCF3, haloalkyl, or optionally substituted C1-C6 alkyl;
y is an integer from 0-6;
or R1 and R23 form a heterocycle that is fused to the phenyl ring;
R2 and R3 are each, independently, H, a protecting group, C(═O)OR81b, optionally substituted aryl, optionally substituted C1-C6 haloalkyl, —R20R21, —NR20R21, optionally substituted C1-C8branched or unbranched alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 haloalkenyl, —(CH2)nR19, optionally substituted cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl, optionally substituted pyridyl, optionally substituted piperidyl, and C3-C6 cyclic ether; such that when X1 is CH, R2 is H or when X2 is C or CH, R3 is H; provided that R2 is not —NR20R21 when X1 is N and R3 is not —NR20R21 when X2 is N, wherein R81b is H or optionally substituted branched or unbranched C1-C6 alkyl;
Z1 is absent or Z1 is C1-C3 alkyl, provided that when Z1 is C1-C3 alkyl, X2 is C;
R4 is a bond, optionally substituted C1-C6 branched or unbranched alkyl or —C═O;
R5 is

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wherein:
R6 and R7 are each, independently, H, halo, cyano, —C(═O)N(R10)2, —NHC(═O)R11, or

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R8 is optionally substituted C1-C6 branched or unbranched alkyl or —(CH2)nOR9;
R9 is optionally substituted C1-C6 branched or unbranched alkyl;
each R10 is, independently, H or optionally substituted C1-C6 branched or unbranched alkyl;
each R11 is, independently, optionally substituted C1-C6 branched or unbranched alkyl;
each R18 is independently H, optionally substituted 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, cyano, optionally substituted C1-C6haloalkyl, —NR20R21 optionally substituted C1-C6 branched or unbranched alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted cycloalkyl, optionally substituted heterocycle, —OH, optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl, optionally substituted pyrazole, optionally substituted ketone, optionally substituted oxazole, optionally substituted thiazole, or optionally substituted piperidyl;
R20 and R21 are, each, independently, H, optionally substituted 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, optionally substituted piperidyl; or R20 and R21 together form a 5-10 membered optionally substituted heterocycle or a 5-10 membered optionally substituted heteroaryl with the atom to which R20 and R21 are bonded to;
R24 is H, optionally substituted alkyl, or optionally substituted C3-C6 cycloalkyl;
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;
R25 is H or optionally substituted C1-C6 alkyl;
R26 is H or optionally substituted C1-C6 alkyl;
R27 is H or optionally substituted C1-C6 alkyl;
R28 is H or optionally substituted C1-C6 alkyl;
R29is H, —NR20R21 or optionally substituted C1-C6 alkyl;
R30 and R31 are each, independently, H, C1-C6 alkyl, —C(═O)C1-C6 alkyl, —S(═O)2C1-C6 alkyl; —S(═O)2(CH2)1-4CF3; —C(═O)O(CH2)1-4Ph; or —C(═O)N(C1-C6 alkyl)2;
R32 is H or optionally substituted C1-C6 alkyl;
and
each n, p, v, and w is, independently, an integer from 0-6.