Poly(adp-ribose) glycohydrolase (parg) inhibitors against covid macrodomain and methods of using the same
OwnerJohn A. TAINER, Zamal AHMED +3inventors
InventorsJohn A. TAINER, Zamal AHMED, Darin E. JONES, Davide MOIANI, Chris Arlen BROSEY
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Abstract
The present disclosure provides compounds of Formula (Ia) and Formula (Ib) and the pharmaceutically acceptable salts and solvates thereof, wherein A1, A2, R1, R2, R3, and R4 are defined as set forth in the specification. The present disclosure also provides the use of compounds of Formula (Ia) or Formula (Ib) to treat a coronavirus infection in a subject.
Claims45
A method for treating or reducing the coronavirus pathogenicity and the symptoms associated with a coronavirus infection, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ia) or Formula (Ib):
- wherein:
- A1 and A2 are independently 0, S, or NH;
- R1 and R2 are independently unsubstituted C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (C3-C6 cycloalkyl)C1-C6 alkyl;
- R3 is H or —X—Y—R5;
- R4 is H or —Y′—R5′;
- X is absent, S, O, or NH;
- Y is —(CH2)n— or —(CH2)m(C═O)—;
- n is an integer of 1, 2, 3, 4, 5, or 6;
- m is an integer of 0, 1, 2, 3, 4, 5, or 6;
- Y′ is —(CH2)n′— or —(CH2)m′(C═O)—;
- n′ is an integer of 1, 2, 3, 4, 5, or 6;
- m′ is an integer of 0, 1, 2, 3, 4, 5, or 6;
- R5 is optionally substituted aryl, optionally substituted 3- to 10-membered heterocyclo,
- A3 is O, S, or NH;
- R6 is optionally substituted C1-C6 alkyl, optionally substituted (3- to 10-membered heterocyclo)C1-C6 alkyl, or S(═O)2R7;
- R7 is optionally substituted C1-C6 alkyl or optionally substituted (3- to 10-membered heterocyclo)C1-C6 alkyl;
- R8 is optionally substituted C1-C6 alkyl or optionally substituted (3- to 10-membered heterocyclo)C1-C6 alkyl;
- R5′ is C1-C4 haloalkyl, hydroxy, C3-C6 cycloalkyl, C1-C4 alkoxy, amino, optionally substituted aryl, optionally substituted 3- to 10-membered heterocyclo,
- A3′ is O, S, or NH;
- R6′ is optionally substituted C1-C6 alkyl, optionally substituted (3- to 10-membered heterocyclo)C1-C6 alkyl, or S(═O)2R7′;
- R7′ is optionally substituted C1-C6 alkyl or optionally substituted (3- to 10-membered heterocyclo)C1-C6 alkyl;
- and
- R8′ is optionally substituted C1-C6 alkyl or optionally substituted (3- to 10-membered heterocyclo)C1-C6 alkyl;
- or a pharmaceutically acceptable salt thereof,
- with the proviso that R3 and R4 are not both H.
A compound of Formula (Ia) or Formula (Ib):
- wherein:
- A1 and A2 are independently O, S, or NH;
- R1 and R2 are independently unsubstituted C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (C3-C6 cycloalkyl)C1-C6 alkyl;
- and
- R3 is H or —X—Y—R5;
- R4 is H or —Y′—R5′;
- X is absent, S, O, or NH;
- Y is —(CH2)n— or —(CH2)m(C═O)—;
- n is an integer of 1, 2, 3, 4, 5, or 6;
- m is an integer of 0, 1, 2, 3, 4, 5, or 6;
- Y′ is —(CH2)n′— or —(CH2)m′(C═O)—;
- n′ is an integer of 1, 2, 3, 4, 5, or 6;
- m′ is an integer of 0, 1, 2, 3, 4, 5, or 6;
- R5 is optionally substituted aryl, optionally substituted 3- to 10-membered heterocyclo,
- A3 is O, S, or NH;
- R6 is optionally substituted C1-C6 alkyl or S(═O)2R7;
- R7 is optionally substituted C1-C6 alkyl, or optionally substituted (3- to 10-membered heterocyclo)C1-C6 alkyl;
- R8 is optionally substituted (3- to 6-membered heterocyclo)C1-C6 alkyl;
- R5′ is C1-C4 haloalkyl, hydroxy, C3-C6 cycloalkyl, C1-C4 alkoxy, amino, optionally substituted aryl, optionally substituted 3- to 10-membered heterocyclo,
- A3′ is O, S, or NH;
- R6′ is optionally substituted C1-C6 alkyl or S(═O)2R7;
- R7′ is optionally substituted C1-C6 alkyl, or optionally substituted (3- to 10-membered heterocyclo)C1-C6 alkyl;
- and
- R8′ is optionally substituted (3- to 6-membered heterocyclo)C1-C6 alkyl;
- or a pharmaceutically acceptable salt thereof,
- with the proviso that R3 and R4 are not both H.
A method for inhibiting coronavirus pathogenicty and symptoms by administering to a subject in need thereof a therapeutically effective amount of a compound that is chemically complementary to the Mac1 channel and interactions defined and implied by the crystal structures of the Mac1/PARG-345 (MES8-4) complex and the Mac1/PARG-329 complex with their neighboring bound water molecules.
Dependencies are inferred from the claim text.