Host targeted inhibitors of dengue virus and other viruses
Novel antiviral compounds of Formulae (I)-(III) are provided: (I) (II) (III) The inventive compounds, pharmaceutical compositions thereof, and kits including the inventive compounds are useful for the prevention and treatment of infectious diseases caused by viruses, for example, by Flaviviridae virus (e.g., Dengue virus (DENY)), Kunjin virus, Japanese encephalitis virus, vesicular stomatitis virus (VSV), herpes simplex virus 1 (HSV-1), human cytomegalovirus (HCMV), poliovirus, Junin virus, Ebola virus, Marburg virus (MARV), Lassa fever virus (LASV), Venezuelan equine encephalitis virus (VEEV), or Rift Valley Fever virus (RVFV).
1. A compound of the formula:
or a pharmaceutically acceptable salt thereof;
wherein:
is Ring A, wherein Ring A is 5 or 6-membered, monocyclic heteroaryl comprising 1 to 4 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or 5,6- or 6,6-membered bicyclic heteroaryl comprising 1 to 4 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and Ring A is optionally substituted with k instances of R A ;
each instance of R A is independently selected from the group consisting of halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted heterocyclyl, —OR A1 , —N(R A1 ) 2 , —SR A1 , —CN, —C(═NR A1 )R A1 , —C(NR A1 )OR A1 , —C(NR A1 )N(R A1 ) 2 , —NO 2 , —N 3 , —NR A1 C(═O)R A1 , —NR A1 C(═O)OR A1 , —NR A1 C(═O)N(R A1 ) 2 , —NR A1 C(═NR A1 )R A1 , —NR A1 C(═NR A1 )OR A1 , —NR A1 C(═NR A1 )N(R A1 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)N(R A1 ) 2 , —OC(═NR A1 )R A1 , —OC(═NR A1 )OR A1 , —OC(═NR A1 )N(R A1 ) 2 , —NR A1 S(═O) 2 R A1 , —NR A1 S(═O) 2 OR A1 , —NR A1 S(═O) 2 N(R A1 ) 2 , —OS(═O) 2 R A1 , —OS(═O) 2 OR A1 , —OS(═O) 2 N(R A1 ) 2 , —S(═O) 2 R A1 , —S(═O) 2 OR A1 , and —S(═O) 2 N(R A1 ) 2 , wherein each occurrence of R A1 is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom;
k is 0, 1, 2, or 3; and
R C is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, —OR C1 , —N(R C1 ) 2 , —SR C1 , —CN, —C(═NR C1 )R C1 , —C(═NR C1 )OR C1 , —C(═NR C1 )N(R C1 ) 2 , —NO 2 , —N 3 , —NR C1 C(═O)R C1 , —NR C1 C(═O)OR C1 , —NR C1 C(═O)N(R C1 ) 2 , —NR C1 C(═NR C1 )R C1 , —NR C1 C(═NR C1 )OR C1 , —NR C1 C(═NR C1 )N(R C1 ) 2 , —OC(═O)R C1 , —OC(═O)OR C1 , —OC(═O)N(R C1 ) 2 , —OC(═NR C1 )R C1 , —OC(═NR C1 )OR C1 , —OC(═NR C1 )N(R C1 ) 2 , —NR C1 S(═O) 2 R C1 , —NR C1 S(═O) 2 OR C1 , —NR C1 S(═O) 2 N(R C1 ) 2 , —OS(═O) 2 R C1 , —OS(═O) 2 OR C1 , —OS(═O) 2 N(R C1 ) 2 , —S(═O) 2 R C1 , —S(═O) 2 OR C1 , and —S(═O) 2 N(R C1 ) 2 , wherein each occurrence of R C1 is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom;
when an optionally substituted moiety referred to above is substituted with one or more substituents at a carbon atom, the one or more substituents at the carbon atom are independently halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR aa , —ON(R bb ) 2 , —N(R bb ) 2 , —N(R bb ) 3 + X − , —N(OR cc )R bb , —SH, —SR aa , —SSR cc , —C(═O)R aa , —CO 2 H, —CHO, —C(OR cc ) 2 , —CO 2 R aa , —OC(═O)R aa , —OCO 2 R aa , —C(═O)N(R bb ) 2 , —OC(═O)N(R bb ) 2 , —NR bb C(═O)R aa , —NR bb CO 2 R aa , —NR bb C(═O)N(R bb ) 2 , —C(═NR bb )R aa , —C(═NR bb )OR aa , —OC(═NR bb )R aa , —OC(═NR bb )OR aa , —C(═NR bb )N(R bb ) 2 , —OC(═NR bb )N(R bb ) 2 , —NR bb C(═NR bb )N(R bb ) 2 , —C(═O)NR bb SO 2 R aa , —NR bb SO 2 R aa , —SO 2 N(R bb ) 2 , —SO 2 R aa , —SO 2 OR aa , —OSO 2 R aa , —S(═O)R aa , —OS(═O)R aa , —Si(R aa ) 3 , —OSi(R aa ) 3 —C(═S)N(R bb ) 2 , —C(═O)SR aa , —C(═S)SR aa , —SC(═S)SR aa , —SC(═O)SR aa , —OC(═O)SR aa , —SC(═O)OR aa , —SC(═O)R aa , —P(═O)(R aa ) 2 , —OP(═O)(R aa ) 2 , —OP(═O)(OR cc ) 2 , —P(═O)(NR bb ) 2 , —OP(═O)(NR bb ) 2 , —NR bb P(═O)(OR cc ) 2 , —NR bb P(═O)(NR bb ) 2 , —P(R cc ) 2 , —OP(R cc ) 2 , —B(R aa ) 2 , —B(OR cc ) 2 , —BR aa (OR cc ), C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, or C 2-10 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; or two geminal hydrogen atoms on the carbon atom are replaced with ═O, ═S, ═NN(R bb ) 2 , ═NNR bb C(═O)R aa , ═NNR bb C(═O)OR aa , —NNR bb S(═O) 2 R aa , ═NR bb , or ═NOR cc ;
when an optionally substituted moiety referred to above is substituted with one or more substituents at a nitrogen atom, the one or more substituents at the nitrogen atom are independently a nitrogen protecting group, —OH, —OR aa , —N(R cc ) 2 , —CN, —C(═O)R aa , —C(═O)N(R cc ) 2 , —CO 2 R aa , —SO 2 R aa , —C(═NR bb )R aa , —C(═NR cc )OR aa , —C(═NR cc )N(R cc ) 2 , —SO 2 N(R cc ) 2 , —SO 2 R cc , —SO 2 OR cc , —SOR aa , —C(═S)N(R cc ) 2 , —C(═O)SR cc , —C(═S)SR cc , —P(═O)(R aa ) 2 , —P(═O)(NR cc ) 2 , C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, or C 2-10 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
wherein:
each instance of R aa is, independently, C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, or phenyl, wherein each of the alkyl, alkenyl, alkynyl, and phenyl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
each instance of R bb is, independently, selected from hydrogen, —OH, —OR aa , —N(R cc ) 2 , —CN, —C(═O)R aa , —C(═O)N(R cc ) 2 , —CO 2 R aa , —SO 2 R aa , —C(═NR cc )OR aa , —C(═NR cc )N(R cc ) 2 , —SO 2 N(R cc ) 2 , —SO 2 R cc , —SO 2 OR cc , —SOR aa , —C(═S)N(R cc ) 2 , —C(═O)SR cc , —C(═S)SR cc , —P(═O)(R aa ) 2 , —P(═O)(NR cc ) 2 , C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, and C 2-10 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
each instance of R cc is, independently, selected from hydrogen, C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, and C 2-10 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
each instance of R dd is, independently, selected from halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR ee , —ON(R ff ) 2 , —N(R ff ) 2 , —N(R ff ) 3 + X − , —N(OR ee )R ff , —SH, —SR ee , —SSR ee , —C(═O)R ee , —CO 2 H, —CO 2 R ee , —OC(═O)R ee , —OCO 2 R ee , —C(═O)N(R ff ) 2 , —OC(═O)N(R ff ) 2 , —NR ff C(═O)R ee , —NR ff CO 2 R ee , —NR ff C(═O)N(R ff ) 2 , —C(═NR ff )OR ee , —OC(═NR ff )R ee , —OC(═NR ff )OR ee , —C(═NR ff )N(R ff ) 2 , —OC(═NR ff )N(R ff ) 2 , —NR ff C(═NR ff )N(R ff ) 2 , —NR ff SO 2 R ee , —SO 2 N(R ff ) 2 , —SO 2 R ee , —SO 2 OR ee , —OSO 2 R ee , —S(═O)R ee , —Si(R ee ) 3 , —OSi(R ee ) 3 , —C(═S)N(R ff ) 2 , —C(═O)SR ee , —C(═S)SR ee , —SC(═S)SR ee , —P(═O)(R ee ) 2 , —OP(═O)(R ee ) 2 , —OP(═O)(OR ee ) 2 , C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups, or two geminal R dd substituents can be joined to form ═O or ═S;
each instance of R ee is, independently, selected from C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
each instance of R ff is, independently, selected from hydrogen, C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
each instance of R gg is, independently, halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OC 1-6 alkyl, —ON(C 1-6 alkyl) 2 , —N(C 1-6 alkyl) 2 , —N(C 1-6 alkyl) 3 + X − , —NH(C 1-6 alkyl) 2 + X − , —NH 2 (C 1-6 alkyl) + X − , —NH 3 + X − , —N(OC 1-6 alkyl)(C 1-6 alkyl), —N(OH)(C 1-6 alkyl), —NH(OH), —SH, —SC 1-6 alkyl, —SS(C 1-6 alkyl), —C(═O)(C 1-6 alkyl), —CO 2 H, —CO 2 (C 1-6 alkyl), —OC(═O)(C 1-6 alkyl), —OCO 2 (C 1-6 alkyl), —C(═O)NH 2 , —C(═O)N(C 1-6 alkyl) 2 , —OC(═O)NH(C 1-6 alkyl), —NHC(═O)(C 1-6 alkyl), —N(C 1-6 alkyl)C(═O)(C 1-6 alkyl), —NHCO 2 (C 1-6 alkyl), —NHC(═O)N(C 1-6 alkyl) 2 , —NHC(═O)NH(C 1-6 alkyl), —NHC(═O)NH 2 , —C(═NH)O(C 1-6 alkyl), —OC(═NH)(C 1-6 alkyl), —OC(═NH)OC 1-6 alkyl, —C(═NH)N(C 1-6 alkyl) 2 , —C(═NH)NH(C 1-6 alkyl), —C(═NH)NH 2 , —OC(═NH)N(C 1-6 alkyl) 2 , —OC(NH)NH(C 1-6 alkyl), —OC(NH)NH 2 , —NHC(NH)N(C 1-6 alkyl) 2 , —NHC(═NH)NH 2 , —NHSO 2 (C 1-6 alkyl), —SO 2 N(C 1-6 alkyl) 2 , —SO 2 NH(C 1-6 alkyl), —SO 2 NH 2 , —SO 2 C 1-6 alkyl, —SO 2 OC 1-6 alkyl, —OSO 2 C 1-6 alkyl, —SOC 1-6 alkyl, —Si(C 1-6 alkyl) 3 , —OSi(C 1-6 alkyl) 3 , —C(═S)N(C 1-6 alkyl) 2 , C(═S)NH(C 1-6 alkyl), C(═S)NH 2 , —C(═O)S(C 1-6 alkyl), —C(═S)SC 1-6 alkyl, —SC(═S)SC 1-6 alkyl, —P(═O)(C 1-6 alkyl) 2 , —OP(═O)(C 1-6 alkyl) 2 , —OP(═O)(OC 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl; or two geminal R gg substituents can be joined to form ═O or ═S;
X − is a counterion; and
when an optionally substituted moiety referred to above is substituted with one or more substituents at a sulfur atom, the one or more substituents at the sulfur atom are independently an sulfur protecting group; and
wherein the heterocyclyl is 3 to 10-membered and monocyclic, and comprises independently 1 to 4 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is a 5-membered or 6-membered, monocyclic heteroaryl ring comprising 1 to 4 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and is optionally substituted with k instances of R A .
3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein
is of formula:
4. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein
is of formula:
5. The compound of claim 1 , wherein the compound is of formula:
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 , wherein the compound is of formula:
or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.
8. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is 5,6- or 6,6-membered bicyclic heteroaryl comprising 1 to 4 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and is optionally substituted with k instances of R A .
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is quinolinyl or isoquinolinyl and is optionally substituted with k instances of R A .
12. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
is of formula:
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
is of formula:
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
is of formula:
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one instance of R A is optionally substituted C 1-6 alkyl or halogen.
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one instance of R A is —N(R A1 ) 2 , —NR A1 C(═O)N(R A1 ) 2 , —NR A1 S(═O) 2 R A1 , or —S(═O) 2 N(R A1 ) 2 .
18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one instance of R A is optionally substituted heterocyclyl.
19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein k is 0.
20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein k is 1 or 2.
21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R C is optionally substituted C 1-6 alkyl.
22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R C is —CH 3 .
23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R C is hydrogen, halogen, or —OR C1 .
24. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
25. The compound of claim 1 , wherein the compound is of formula:
or a pharmaceutically acceptable salt thereof.