Host targeted inhibitors of dengue virus and other viruses

Patent metadata

Field	Value
Publication number	US-9879003-B2
Application number	US-201314391638-A
Country	US
Kind code	B2
Filing date	Mar 15, 2013
Priority date	Apr 11, 2012
Publication date	Jan 30, 2018
Grant date	Jan 30, 2018

Abstract

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).

First claim

What is claimed is:

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

Assignees

• Harvard College
• Dana Farber Cancer Inst Inc

Inventors

• Gray Nathanael
• Yang Priscilla
• Liu Qingsong
• De Wispelaere Mélissanne

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title