US 11,739,104 B2
Compositions and methods for inhibiting group II intron RNA
Anna Pyle, Guilford, CT (US); Olga Fedorova, Hamden, CT (US); Erik Gunnar Jagdmann, Branford, CT (US); Michael Van Zandt, Guilford, CT (US); Lin Yuan, Guilford, CT (US); and Albert DeBerardinis, West Hartford, CT (US)
Assigned to YALE UNIVERSITY, New Haven, CT (US)
Appl. No. 16/964,621
Filed by YALE UNIVERSITY, New Haven, CT (US)
PCT Filed Jan. 25, 2019, PCT No. PCT/US2019/015086
§ 371(c)(1), (2) Date Jul. 24, 2020,
PCT Pub. No. WO2019/147894, PCT Pub. Date Aug. 1, 2019.
Claims priority of provisional application 62/622,287, filed on Jan. 26, 2018.
Prior Publication US 2021/0139512 A1, May 13, 2021
Int. Cl. C07D 307/80 (2006.01); C07F 5/02 (2006.01); A61P 31/10 (2006.01); C07C 49/84 (2006.01); C07C 233/65 (2006.01); C07C 233/73 (2006.01); C07C 243/38 (2006.01); C07D 207/08 (2006.01); C07D 211/16 (2006.01); C07D 217/04 (2006.01); C07D 233/64 (2006.01); C07D 239/26 (2006.01); C07D 277/24 (2006.01); C07D 277/26 (2006.01); C07D 277/66 (2006.01); C07D 295/192 (2006.01); C07D 295/215 (2006.01); C07D 307/52 (2006.01); C07D 307/83 (2006.01); C07D 405/04 (2006.01); C07D 405/12 (2006.01); C07D 413/04 (2006.01)
CPC C07F 5/027 (2013.01) [A61P 31/10 (2018.01); C07C 49/84 (2013.01); C07C 233/65 (2013.01); C07C 233/73 (2013.01); C07C 243/38 (2013.01); C07D 207/08 (2013.01); C07D 211/16 (2013.01); C07D 217/04 (2013.01); C07D 233/64 (2013.01); C07D 239/26 (2013.01); C07D 277/24 (2013.01); C07D 277/26 (2013.01); C07D 277/66 (2013.01); C07D 295/192 (2013.01); C07D 295/215 (2013.01); C07D 307/52 (2013.01); C07D 307/80 (2013.01); C07D 307/83 (2013.01); C07D 405/04 (2013.01); C07D 405/12 (2013.01); C07D 413/04 (2013.01)] 12 Claims
 
1. A compound of Formula (I), or a salt thereof;

OG Complex Work Unit Chemistry
wherein:
X is O, S, or NR10;
R1 is H;
R2, R3, and R4 are each independently selected from the group consisting of —OH, —OC(═O)R11, and —OC(═O)OR11;
R5 is H;
R6 is selected from the group consisting of H, —C1-C6 alkyl, —C1-C6 fluoroalkyl, —C1-C6 heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, F, Cl, Br, I, —CN, —NO2, —OR11, —SR11, —S(═O)R11, —S(═O)2R11, —NHS(═O)2R11, —C(═O)R11, —OC(═O)R11, —CO2R11, —OCO2R11, —CH(R11)2, —N(R11)2, —C(═O)N(R11)2, —C(═O)NHR11, —OC(═O)N(R11)2, —NHC(═O)NH(R11), —NHC(═O)R11, —NHC(═O)OR11, —C(OH)(R11)2, and —C(NH2)(R11)2,
wherein each occurrence of R11 in R6 is independently selected from the group consisting of —C1-C6 alkyl, —C1-C6 fluoroalkyl, —C1-C6 heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, and —OH;
R7 and R8 are selected such that only one of the following conditions is met:
(i) R7 is represented by Formula (IV):

OG Complex Work Unit Chemistry
wherein in Formula (IV):
* represents the attachment to Formula (I);
A1, A2, A3, and A4 are independently CR13 or N;
R12 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 perfluoroalkyl, C1-C6 heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, F, Cl, Br, I, —CN, —NO2, —OH, —OR14, —SR14, —S(═O)R14, —S(═O)2R14, —S(═O)2NHR14, —S(═O)2N(R14)2, —NHS(═O)2R14, —C(═O)R14, —OC(═O)R14, —CO2R14, —OCO2R14, —CH(R14)2, —N(R14)2, —C(═O)N(R14)2, —C(═O)NHR14, —OC(═O)N(R14)2, —NHC(═O)NH(R14), —NHC(═O)R14, —NHC(═O)OR14, —C(OH)(R14)2, and —C(NH2)(R14)2;
each occurrence of R13 is independently selected from the group consisting of H, C1-C6 alkyl, F, Cl, Br, I, —CN, —NO2, —OH, —CF3, C1-C6 heteroalkyl, aryl-(C1-C3)alkyl, and cycloalkyl;
or optionally two adjacent R13 are joined to form a ring;
each occurrence of R14 is independently selected from the group consisting of H, C1-C6 alkyl, F, Cl, Br, I, —CN, —NO2, —OH, —CF3, C1-C6 heteroalkyl, aryl-(C1-C3)alkyl, and cycloalkyl;
or optionally two R14 on the same atom may together form a ring; and
R8 is selected from the group consisting of H, —C1-C6 alkyl, —C1-C6 fluoroalkyl, —C1-C6 heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, F, Cl, Br, I, —CN, —NO2, —OH, —OR11, —SR11, —S(═O)R11, —S(═O)2R11, —NHS(═O)2R11, —C(═O)R11, —OC(═O)R11, —CO2R11, —OCO2R11, —CH(R11)2, —N(R11)2, —C(═O)N(R11)2, —C(═O)NHR11, —OC(═O)N(R11)2, —NHC(═O)NH(R11), —NHC(═O)R11, —NHC(═O)OR11, —C(OH)(R11)2, and —C(NH2)(R11)2;
(ii) R7 is selected from the group consisting of H, —C1-C6 alkyl, —C1-C6 fluoroalkyl, —C1-C6 heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, F, Cl, Br, I, —CN, —NO2, —OH, —OR11, —SR11, —S(═O)R11, —S(═O)2R11, —NHS(═O)2R11, —C(═O)R11, —OC(═O)R11, —CO2R11, —OCO2R11, —CH(R11)2, —N(R11)2, —C(═O)N(R11)2, —C(═O)NHR11, —OC(═O)N(R11)2, —NHC(═O)NH(R11), —NHC(═O)R11, —NHC(═O)OR11, —C(OH)(R11)2, and —C(NH2)(R11)2; and
R8 is selected from the group consisting of —C1-C6 fluoroalkyl, —C1-C6 heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, —CN, —NO2, —SR11, —S(═O)R11, —S(═O)2R11, —NHS(═O)2R11, —C(═O)R11, —CO2R11, —OCO2R11, —CH(R11)2, —N(R11)2, —C(═O)N(R11)2, —C(═O)NHR11, —OC(═O)N(R11)2, —NHC(═O)NH(R11), —NHC(═O)R11, —NHC(═O)OR11, —C(OH)(R11)2, and —C(NH2)(R11)2;
R9 and R10 are each independently selected from the group consisting of H, —C1-C6 alkyl, —C1-C6 fluoroalkyl, —C1-C6 heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, F, Cl, Br, I, —CN, —NO2, —OH, —OR11, —SR11, —S(═O)R11, —S(═O)2R11, —NHS(═O)2R11, —C(═O)R11, —OC(═O)R11, —CO2R11, —OCO2R11, —CH(R11)2, —N(R11)2, —C(═O)N(R11)2, —C(═O)NHR11, —OC(═O)N(R11)2, —NHC(═O)NH(R11), —NHC(═O)R11, —NHC(═O)OR11, —C(OH)(R11)2, and —C(NH2)(R11)2;
each occurrence of R11 in R2, R3, R4, R7, R8, R9, or R10 is independently selected from the group consisting of H, —C1-C6 alkyl, —C1-C6 fluoroalkyl, —C1-C6 heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, and —OH; and
the bond between carbons 1 and 2, the bond between carbons 2 and 3, Y, and Z are selected such that only one of the two following conditions is met:
(a) the bond between carbons 1 and 2 is a single bond, the bond between carbons 2 and 3 is a double bond, Y is (═O), and Z is H; or
(b) the bond between carbons 1 and 2 is a double bond, the bond between carbons 2 and 3 is a single bond, Y is H, and Z is (═O).