Compounds and methods for the treatment or prevention of flavivirus infections
Compounds represented by formula I: or pharmaceutically acceptable salts and solvates thereof, wherein R 1 , X, Y, Y 1 , and Z are as defined herein, are useful for treating flaviviridae viral infections.
1. A process for preparing a compound of formula (I)
comprising reacting a compound of formula (II):
with a compound of formula R 1 —B(OH) 2 or R 1 —Bi,
wherein,
R 1 is chosen from optionally substituted C 3-12 cycloalkyl, optionally substituted —C(O)—C 3-12 cycloalkyl, optionally substituted 5 to 12 member spiroheterocycloalkyl and optionally substituted 8 to 12 member spiroheterocycloalkenyl;
X is chosen from:
M is chosen from:
and a bond;
R 2 , R 3 and R 6 are each independently chosen from H, optionally substituted C 1-12 alkyl, optionally substituted C 2-12 alkenyl, optionally substituted C 2-12 alkynyl, optionally substituted C 6-14 aryl, optionally substituted C 7-16 aralkyl, optionally substituted 5-12 member heteroaryl, optionally substituted 6-18 member heteroaralkyl, optionally substituted 3-12 member heterocycle, and optionally substituted 4-18 member heterocycle-alkyl;
R 4 and R 5 are each independently chosen from H, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl and optionally substituted C 2-6 alkynyl;
Y 1 is a bond, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, or optionally substituted C 2-6 alkynyl;
Y is COOR 9 , COCOOR 9 , P(O)OR a OR b , S(O)OR 9 , S(O) 2 OR 9 , tetrazole, CON(R 9 )CH(R 9 )COOR 9 , CONR 10 R, R 11 , CON(R 9 )—SO 2 —R 9 , CONR 9 OH, or halogen;
J is chosen from:
R 7 is chosen from H, optionally substituted C 1-12 alkyl, optionally substituted C 2-12 alkenyl optionally substituted, optionally substituted C 2-12 alkynyl, optionally substituted C 6-14 aryl and optionally substituted C 7-16 aralkyl;
W is chosen from O, S and NR 8 ;
R 8 is chosen from H, optionally substituted C 1-12 alkyl, optionally substituted C 2-12 alkenyl, optionally substituted C 2-12 alkynyl, optionally substituted C 6-14 aryl, optionally substituted C 7-16 aralkyl, optionally substituted 5-12 member heteroaryl, optionally substituted 6-18 member heteroaralkyl, optionally substituted 3-12 member heterocycle, and optionally substituted 4-18 member heterocycle-alkyl;
R 9 , R 10 and R 11 are each independently chosen from H, optionally substituted C 1-12 alkyl, optionally substituted C 2-12 alkenyl, optionally substituted C 2-12 alkynyl, optionally substituted C 6-14 aryl, optionally substituted C 7-16 aralkyl, optionally substituted 5-12 member heteroaryl, optionally substituted 6-18 member heteroaralkyl, optionally substituted 3-12 member heterocycle, or optionally substituted 4-18 member heterocycle-alkyl,
or R 10 and R 11 are taken together with the nitrogen atom to form an optionally substituted 3 to 10 member heterocycle or an optionally substituted 5-12 member heteroaryl;
Pg 1 is OH, methoxy or a carboxyl protecting group;
Hal is Cl, Br, or I; and
B 1 is a boronate;
under Suzuki coupling conditions to form a compound of formula (I).
2. The process according to claim 1 , wherein Hal is Br.
3. The process according to claim 1 , wherein Pg 1 is methoxy.
4. The process according to claim 1 , wherein R 1 is optionally substituted C 3-12 cycloalkyl.
5. The process according to claim 1 , wherein X is
and M is
or a bond.
6. The process according to claim 5 , wherein M is
7. The process according to claim 1 , wherein R 2 is optionally substituted C 1-12 alkyl.
8. The process according to claim 7 , wherein R 2 is optionally substituted cyclohexyl.
9. The process according to claim 8 , wherein R 2 is methylcyclohexyl.
10. The process according to claim 1 , wherein R 3 is optionally substituted C 1-12 alkyl.
11. The process according to claim 10 , wherein R 3 is optionally substituted cyclohexyl.
12. The process according to claim 11 , wherein R 3 is hydroxycyclohexyl or methoxycyclohexyl.
13. The process according to claim 1 , wherein R 1 —B(OH) 2 is
14. The process according to claim 1 , wherein Y 1 is a bond.
15. The process according to claim 1 , wherein Y is COOH, CONH 2 , CONHCH 2 COOH, or COOCH 3 .
16. The process according to claim 1 , wherein R 9 , R 10 , and R 11 are each independently H or methyl.