US 12,234,240 B2
Substituted imidazo[5,1-d][1,2,3,5]tetrazines for the treatment of cancer
Paul J. Hergenrother, Champaign, IL (US); Timothy M. Fan, Mahomet, IL (US); and Riley L. Svec, Urbana, IL (US)
Assigned to The Board of Trustees of the University of Illinois, Urbana, IL (US)
Filed by The Board of Trustees of the University of Illinois, Urbana, IL (US)
Filed on Dec. 16, 2022, as Appl. No. 18/067,531.
Application 18/067,531 is a continuation of application No. 17/017,475, filed on Sep. 10, 2020, abandoned.
Application 17/017,475 is a continuation in part of application No. PCT/US2019/045986, filed on Aug. 9, 2019.
Claims priority of provisional application 62/873,669, filed on Jul. 12, 2019.
Claims priority of provisional application 62/778,750, filed on Dec. 12, 2018.
Claims priority of provisional application 62/716,390, filed on Aug. 9, 2018.
Prior Publication US 2023/0183252 A1, Jun. 15, 2023
Prior Publication US 2024/0124462 A9, Apr. 18, 2024
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/519 (2006.01); A61K 9/20 (2006.01); A61K 9/48 (2006.01); A61K 31/495 (2006.01); A61K 47/02 (2006.01); A61K 47/24 (2006.01); A61K 47/26 (2006.01); A61K 47/34 (2017.01); A61K 47/36 (2006.01); C07D 487/04 (2006.01)
CPC C07D 487/04 (2013.01) [A61K 9/2009 (2013.01); A61K 9/2013 (2013.01); A61K 9/2018 (2013.01); A61K 9/2027 (2013.01); A61K 9/2054 (2013.01); A61K 9/2059 (2013.01); A61K 9/485 (2013.01); A61K 9/4858 (2013.01); A61K 9/4866 (2013.01); A61K 31/495 (2013.01); A61K 47/02 (2013.01); A61K 47/24 (2013.01); A61K 47/26 (2013.01); A61K 47/34 (2013.01); A61K 47/36 (2013.01)] 13 Claims
 
1. A compound of Formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof,
wherein:
R1 is 5- or 6-membered heterocycloalkyl, wherein the 5- or 6-membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I, CN, NO2, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)1-2NHC(O)R′, C(NH)N(R′)2, C(NOR′)R′, C(O)R′, C(O)CH2C(O)R′, C(O)C(O)R′, C(O)N(R′)2, C(O)N(OR)R′, C(O)OR', C(S)R′, C(S)N(R′)2, N(R′)2, NR′C(O)R′, NR′C(O)N(R′)2, NR′C(O)OR″, NR′C(S)R′, NR′C(S)(R′)2, NR′NR′C(O)R′, NR′NR′CON(R′)2, NR′NR′C(O)OR', NR′S(O)2R′, NR′S(O)2N(R′)2, N[C(O)R′]C(O)R′, N(OR′)R′, OR′, OCF3, —OCH2O—, —OCH2CH2O—, OC(O)R′, OC(O)N(R′)2, ═O, SR′, S(O)R′, S(O)2R′, S(O)2N(R′)2, S(O)2OR′, ═S, and C3-C6 cycloalkyl;
R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl;
wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I, CN, NO2, (CH2)1-2NHC(O)R′, C(NH)N(R′)2, C(NOR′)R′, C(O)R′, C(O) CH2C(O)R′, C(O)C(O)R′, C(O)N(R′)2, C(O)N(OR)R′, C(O)OR′, C(S)R′, C(S)N(R′)2, N(R′)2, NR′C(O)R′, NR′C(O)N(R′)2, NR′C(O)OR', NR′C(S)R′, NR′C(S)N(R′)2, NR′NR′C(O)R′, NR′NR′CON(R′)2, NR′NR′C(O)OR′, NR′S(O)2R′, NR′S(O)2N(R′)2, N[C(O)R′]C(O)R′, N(OR′)R′, OR′, OCF3, —OCH2O—, —OCH2CH2O—, OC(O)R′, OC(O)N(R′)2, SR′, S(O)R′, S(O)2R′, S(O)2N(R′)2, S(O)2OR′, and C3-C6 cycloalkyl; and
wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I, CN, NO2, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)1-2NHC(O)R′, C(NH)N(R′)2, C(NOR′)R′, C(O)R′, C(O)CH2C(O)R′, C(O)C(O)R′, C(O)N(R′)2, C(O)N(OR)R′, C(O)OR′, C(S)R′, C(S)N(R′)2, N(R′)2, NR′C(O)R′, NR′C(O)N(R′)2, NR′C(O)OR', NR′C(S)R′, NR′C(S)N(R′)2, NR′NR′C(O)R′, NR′NR′CON(R′)2, NR′NR′C(O)OR′, NR′S(O)2R′, NR′S(O)2N(R′)2, N[C(O)R′]C(O)R′, N(OR′)R′, OR′, OCF3, —OCH2O—, —OCH2CH2O—, OC(O)R′, OC(O)N(R′)2, ═O, O(phenyl), SR′, S(O)R′, S(O)2R′, S(O)2N(R′)2, S(O)2OR′, ═S, and C3-C6 cycloalkyl;
R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl;
wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I, CN, NO2, (CH2)1-2NHC(O)R′, C(NH)N(R′)2, C(NOR′)R′, C(O)R′, C(O)CH2C(O)R′, C(O)C(O)R′, C(O)N(R′)2, C(O)N(OR)R′, C(O)OR′, C(S)R′, C(S)N(R′)2, N(R′)2, NR′C(O)R′, NR′C(O)N(R′)2, NR′C(O)OR′, NR′C(S)R′, NR′C(S)N(R′)2, NR′NR′C(O)R′, NR′NR′CON(R′)2, NR′NR′C(O)OR′, NR′S(O)2R′, NR′S(O)2N(R′)2, N[C(O)R′]C(O)R′, N(OR′)R′, OR′, OCF3, —OCH2O—, —OCH2CH2O—, OC(O)R′, OC(O)N(R′)2, SR′, S(O)R′, S(O)2R′, S(O)2N(R′)2, S(O)2OR′, and C3-C6 cycloalkyl; and
wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I, CN, NO2, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)1-2NHC(O)R′, C(NH)N(R′)2, C(NOR′)R′, C(O)R′, C(O)CH2C(O)R′, C(O)C(O)R′, C(O)N(R′)2, C(O)N(OR)R′, C(O)OR′, C(S)R′, C(S)N(R′)2, N(R′)2, NR′C(O)R′, NR′C(O)N(R′)2, NR′C(O)OR′, NR′C(S)R′, NR′C(S)N(R′)2, NR′NR′C(O)R′, NR′NR′CON(R′)2, NR′NR′C(O)OR′, NR′S(O)R′, NR′S(O)2N(R′)2, N[C(O)R′]C(O)R′, N(OR′)R′, OR′, OCF3, —OCH2O—, —OCH2CH2O—, OC(O)R′, OC(O)N(R′)2, ═O,SR′, S(O)R′, S(O)2R′, S(O)2N(R′)2, S(O)2OR′, ═S, and C3-C6 cycloalkyl;
each R′ is independently H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; and
X is O or S.